U.S. patent number 8,119,633 [Application Number 12/112,592] was granted by the patent office on 2012-02-21 for substituted sulfonamide compounds.
This patent grant is currently assigned to Gruenenthal GmbH. Invention is credited to Edward Bijsterveld, Werner Englberger, Heinz Graubaum, Sabine Hees, Ruth Jostock, Beatrix Merla, Stefan Oberboersch, Melanie Reich, Timo Struenker, Bernd Sundermann, Fritz Theil.
United States Patent |
8,119,633 |
Merla , et al. |
February 21, 2012 |
Substituted sulfonamide compounds
Abstract
Substituted sulfonamide compounds corresponding to formula I
##STR00001## pharmaceutical compositions comprising them, a process
for preparing them, and the use of such compounds to treat or
inhibit pain and other disorders or disease states.
Inventors: |
Merla; Beatrix (Aachen,
DE), Oberboersch; Stefan (Aachen, DE),
Reich; Melanie (Aachen, DE), Sundermann; Bernd
(Friedrichsdorf, DE), Englberger; Werner (Stolberg,
DE), Struenker; Timo (Cologne, DE),
Jostock; Ruth (Stolberg, DE), Hees; Sabine
(Aachen, DE), Bijsterveld; Edward (Nijmegen,
NL), Theil; Fritz (Berlin, DE), Graubaum;
Heinz (Berlin, DE) |
Assignee: |
Gruenenthal GmbH (Aachen,
DE)
|
Family
ID: |
39673041 |
Appl.
No.: |
12/112,592 |
Filed: |
April 30, 2008 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20080312231 A1 |
Dec 18, 2008 |
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Foreign Application Priority Data
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Apr 30, 2007 [DE] |
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10 2007 020 492 |
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Current U.S.
Class: |
514/234.8;
544/383; 544/119; 514/255.01; 514/562; 562/432 |
Current CPC
Class: |
A61P
19/02 (20180101); A61P 13/12 (20180101); A61P
25/32 (20180101); A61P 37/08 (20180101); A61P
1/12 (20180101); A61P 25/36 (20180101); A61P
17/00 (20180101); A61P 11/06 (20180101); A61P
13/10 (20180101); C07D 211/96 (20130101); C07D
295/135 (20130101); C07D 211/26 (20130101); A61P
29/00 (20180101); A61P 25/24 (20180101); A61P
11/00 (20180101); A61P 25/22 (20180101); A61P
17/06 (20180101); A61P 3/04 (20180101); A61P
25/04 (20180101); A61P 43/00 (20180101); A61P
1/04 (20180101); A61P 9/00 (20180101); A61P
13/08 (20180101); A61P 25/00 (20180101); A61P
3/10 (20180101); A61P 25/06 (20180101); A61P
31/04 (20180101); A61P 9/10 (20180101) |
Current International
Class: |
A61K
31/5377 (20060101); A61P 25/24 (20060101); A61P
25/00 (20060101); A61K 31/495 (20060101); C07D
413/02 (20060101); A61P 25/06 (20060101); A61P
3/10 (20060101); C07D 241/04 (20060101); A61P
3/04 (20060101); A61K 31/192 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
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6319920 |
November 2001 |
Caroon et al. |
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Foreign Patent Documents
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2001172257 |
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Jun 2001 |
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JP |
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WO 2004/092164 |
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Oct 2004 |
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WO |
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WO 2007/115821 |
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Oct 2007 |
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WO |
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Other References
Sara H. Bengtson, et al, "Kinin Receptor Expression during
Staphylococcus aureus Infection", Blood, Sep. 15, 2006, pp.
2055-2063, vol. 108, No. 6, The American Society of Hematology,
Washington, DC, USA. cited by other .
Gabra et al., The kinin system mediates hyperalgesia through the
inducible bradykinin B1 receptor subtype: evidence in various
experimental animal models of type 1 and type 2 diabetic
neuropathy, Biol. Chem. vol. 387, pp. 127-143, Feb. 2006. cited by
other .
Joao B. Calixto, et al., "Kinin B.sub.1 Receptors: Key
G-Protein-Coupled Receptors and their Role in Inflammatory and
Painful Processes", British Journal of Pharmacology, 2004, pp.
803-818, vol. 143, Nature Publishing Group. cited by other .
R. Hayashi et al., "Bradykinin Stimulates IL-6 and IL-8 Production
by Human Lung Fibroblasts through ERK- and p38 MAPK-dependent
Mechanisms", European Respiratory Journal, 2000, pp. 452-458, vol.
16, ERS Journals Ltd. cited by other .
L.M. Fredrik Leeb-Lundberg et al., "International Union of
Pharmacology. XLV. Classification of the Kinin Receptor Family:
from Molecular Mechanisms to Pathophysiological Consequences",
Pharmacological Reviews, 2005, pp. 27-77, vol. 57, No. 1, The
American Society for Pharmacology and Experimental Therapeutics,
USA. cited by other .
Hess et al., Generation and characterization of a humanized
bradykinin B1 receptor mouse, Biol. Chem., vol. 387, pp. 195-201,
Feb. 2006. cited by other .
Giselle F. Passos et al., "Kinin B.sub.1 Receptor Up-Regulation
after Lipopolysaccharide Administration: Role of Proinflammatory
Cytokines and Neutrophil Influx.sup.1", The Journal of Immunology,
2004, pp. 1839-1847, vol. 172, The American Association of
Immunologists, Inc. cited by other .
Joao B. Pesquero et al., "Hypoalgesia and Altered Inflammatory
Responses in Mice Lacking Kinin B1 Receptors", PNAS, Jul. 5, 2000,
pp. 8140-8145, vol. 97, No. 14. cited by other .
Joao B. Pesquero et al., "Genetically Altered Animal Models in the
Kallikrein-Kinin System", Biol. Chem., Feb. 2006, pp. 119-126, vol.
387. cited by other .
A. Prat et al, "Bradykinin B.sub.1 Receptor Expression and Function
on T Lymphocytes in Active Multiple Sclerosis", Neurology, Dec. 10,
1999, pp. 2087-2092, vol. 53, No. 9, 1999 American Academy of
Neurology. cited by other .
Antoni Stadnicki et al., "Immunolocalization and Expression of
Kinin B.sub.1R and B.sub.2R Receptors in Human Inflammatory Bowel
Disease", Am. J. Physiol. Gastrointest. Liver Physiol., Mar. 31,
2005, pp. G361-G366, vol. 289, American Physiological Society.
cited by other .
International Search Report and Written Opinion, mailed Aug. 21,
2008. cited by other.
|
Primary Examiner: Chu; Yong
Attorney, Agent or Firm: Crowell & Moring LLP
Claims
What is claimed is:
1. A substituted sulfonamide compound corresponding to formula I:
##STR00036## wherein m represents 0, 1 or 2, n represents 0, 1 or
2, p represents 1, q represents 0 or 1, A represents CH--NH--,
CH--CH.sub.2--NH-- or CH--CH.sub.2--CH.sub.2--NH, wherein
individual hydrogen atoms can also be replaced by C.sub.1-5-alkyl,
R.sup.1 and R.sup.2 each independently denote H; C.sub.1-6-alkyl;
or phenyl linked via a C.sub.1-3-alkyl chain, with the proviso that
R.sup.1 and R.sup.2 are not both H; R.sup.3 represents aryl or
heteroaryl, in each case unsubstituted or mono- or
poly-substituted; or aryl linked via a C.sub.1-3-alkyl chain and in
each case unsubstituted or mono- or poly-substituted; R.sup.4 and
R.sup.4a each independently represent H, C.sub.1-6-alkyl, in each
case saturated or unsaturated, branched or unbranched,
unsubstituted or mono- or poly-substituted; F; Cl; aryl, in each
case unsubstituted or mono- or poly-substituted; or aryl linked via
a C.sub.1-3-alkyl chain and in each case unsubstituted or mono- or
poly-substituted; R.sup.5 and R.sup.5a each independently represent
H; or C.sub.1-6-alkyl, in each case saturated or unsaturated,
branched or unbranched, unsubstituted or mono- or poly-substituted;
OH, OC.sub.1-6-alkyl, F, Cl, phenoxy or benzyloxy; Q denotes a
single bond, --CH.sub.2-- or --CH.sub.2--CH.sub.2--; R.sup.6
represents H; C.sub.1-6-alkyl, in each case saturated or
unsaturated, branched or unbranched, unsubstituted or mono- or
poly-substituted; C.sub.3-8-cycloalkyl, saturated or unsaturated,
unsubstituted or mono- or poly-substituted; aryl or heteroaryl,
unsubstituted or mono- or poly-substituted; aryl or
C.sub.3-8-cycloalkyl linked via a C.sub.1-3-alkyl chain; or R.sup.6
together with Q and including the adjacent nitrogen represents
##STR00037## R.sup.7 represents aryl or heteroaryl, in each case
unsubstituted or mono- or poly-substituted; wherein substituents of
mono- or poly-substituted alkyl or cycloalkyl groups are selected
from the group consisting of F, Cl, Br, I, CN, NH.sub.2,
NH--C.sub.1-6-alkyl, NH--C.sub.1-6-alkyl-OH, C.sub.1-6-alkyl,
N(C.sub.1-6-alkyl).sub.2, N(C.sub.1-6-alkyl-OH).sub.2, NO.sub.2,
SH, S--C.sub.1-6-alkyl, S-benzyl, O--C.sub.1-6-alkyl, OH,
O--C.sub.1-6-alkyl-OH, .dbd.O, O-benzyl, C(.dbd.O)C.sub.1-6-alkyl,
CO.sub.2H, CO.sub.2--C.sub.1-6-alkyl, phenyl and benzyl; and
wherein substituents of mono- or poly-substituted aryl or
heteroaryl groups are selected from the group consisting of F, Cl,
Br, I, CN, NH.sub.2, NH--C.sub.1-6-alkyl, NH--C.sub.1-6-alkyl-OH,
N(C.sub.1-6-alkyl).sub.2, N(C.sub.1-6-alkyl-OH).sub.2, NO.sub.2,
SH, S--C.sub.1-6-alkyl, OH, O--C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl-OH, C(.dbd.O)C.sub.1-6-alkyl, CO.sub.2H,
CH.sub.2SO.sub.2-phenyl, CO.sub.2--C.sub.1-6-alkyl, OCF.sub.3,
CF.sub.3, ##STR00038## C.sub.1-6-alkyl, phenyl, pyridyl, thienyl
and furyl; or a salt thereof with a physiologically acceptable
acid.
2. A substituted sulfonamide compound according to claim 1, wherein
said compound is present in the form of an isolated
stereoisomer.
3. A substituted sulfonamide compound according to claim 1, wherein
said compound is present in the form of a mixture of
stereoisomers.
4. A substituted sulfonamide compound according to claim 1, wherein
said compound is present in the form of a racemic mixture.
5. A substituted sulfonamide compound according to claim 1, wherein
R.sup.1 and R.sup.2 each independently denote H; CH.sub.3;
C.sub.2H.sub.5; or phenyl linked via a C.sub.1-3-alkyl chain, with
the provisio that R.sup.1 and R.sup.2 are not both H.
6. A substituted sulfonamide compound according to claim 1, wherein
R.sup.3 represents 2-thienyl, 4-fluorophenyl, 3-fluorophenyl,
4-chlorophenyl, phenethyl, phenyl or benzyl.
7. A substituted sulfonamide compound according to claim 1, wherein
R.sup.4 and R.sup.4a each represent H.
8. A substituted sulfonamide compound according to claim 1, wherein
R.sup.5 and R.sup.5a each represent H.
9. A substituted sulfonamide compound according to claim 1, wherein
R.sup.6 represents methyl, ethyl or benzyl and Q represents a
single bond.
10. A substituted sulfonamide compound according to claim 9,
wherein R.sup.6 denotes methyl.
11. A substituted sulfonamide compound according to claim 1,
wherein the group ##STR00039## of formula I represents
##STR00040##
12. A substituted sulfonamide compound according to claim 1,
wherein the group ##STR00041## of formula I represents ##STR00042##
m represents 0, 1 or 2; n represents 0; q represents 0; and R.sup.5
and R.sup.5a each represent H; or Q represents a single bond; m
represents 0, 1 or 2; n represents 1 or 2; q represents 0; R.sup.4
and R.sup.4a each represent H; R.sup.5 and R.sup.5a each represent
H; and R.sup.6 represents H or C.sub.1-6-alkyl.
13. A substituted sulfonamide compound according to claim 1,
wherein A represents NH--CH, NH--CH.sub.2--CH or
NH--CH.sub.2--CH.sub.2--CH, wherein individual hydrogen atoms can
also be replaced by C.sub.1-5-alkyl; R.sup.1 and R.sup.2 each
independently represent C.sub.1-6-alkyl and R.sup.3 represents
aryl, which optionally may be linked via a C.sub.1-3-alkyl group,
wherein the aryl is in each case unsubstituted or mono- or
poly-substituted by identical or different substituents
independently selected from the group consisting of methyl, ethyl,
methoxy, ethoxy, F, Cl, Br, CN, CF.sub.3, OCF.sub.3 and OH.
14. A compound according to claim 13, wherein R.sup.1 and R.sup.2
each independently represent methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, isobutyl or tert-butyl, and R.sup.3 represents
phenyl or furanyl.
15. A substituted sulfonamide compound according to claim 1,
wherein the group ##STR00043## in formula I represents ##STR00044##
m represents 1 or 2; n and q each represent 0; R.sup.5 and R.sup.5a
each represent H; A represents NH--CH or NH--CH.sub.2--CH; R.sup.1
and R.sup.2 each independently represent C.sub.1-6-alkyl; and
R.sub.3 represents phenyl, wherein the phenyl is in each case
unsubstituted or mono- or poly-substituted by identical or
different substituents independently selected from the group
consisting of methyl, ethyl, methoxy, ethoxy, F, Cl, Br, CN,
CF.sub.3, OCF.sub.3 and OH,
16. A substituted sulfonamide compound according to claim 15,
wherein: m represents 1; A represents NH--CH; R.sup.1 and R.sup.2
each independently represent methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, isobutyl or tert-butyl; or the phenyl group in
R.sub.3 is mono- or polysubstituted by substituents independently
selected from the group consisting of methyl, methoxy, F, Cl, Br,
CN, CF.sub.3 and OH.
17. A substituted sulfonamide compound according to claim 1,
wherein R.sup.7 represents 2,4-dichlorophenyl,
2,4,6-trichlorophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl,
2,6-dimethyl-4-methoxyphenyl or 3,4-dichlorophenyl.
18. A substituted sulfonamide compound according to claim 1,
wherein said compound is selected from the group consisting of: (1)
N-(3-{3-[4-(dimethylaminophenylmethyl)cyclohexyl]ureido}propyl)-4-methoxy-
-2,3,6,N-tetramethylbenzenesulfonamide; (5)
5-[methyl-(2,4,6-trichloro-benzenesulfonyl)-amino]-pentanecarboxylic
acid [4-(dimethylamino-phenyl-methyl)-cyclohexyl]-amide; (7)
5-[methyl-(2,4,6-trichloro-benzenesulfonyl)-amino]-pentanecarboxylic
acid [4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]-amide; (8)
N-[4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]-2-[1-(3-trifluoro-me-
thyl-benzenesulfonyl)-piperidin-2-yl]-acetamide; (9)
N-[4-(dimethylamino-phenyl-methyl)-cyclohexyl]-2-[2-(4-methoxy-benzene
-sulfonyl)-1, 2, 3,4-tetrahydro-isoquinolin-1-yl]-acetamide; (10)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-l-yl]--
N-[4-(dimethylamino-phenyl-methyl)-cyclohexyl]-acetamide; (13)
N-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexyl}-2-[2-(4-methoxy-
-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide;
(14)
N-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexyl}-2-[2-(4-methoxy-
-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-l-yl]-acetamide;
(15)
N-[4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexyl]-2-[2-(4-methoxy-ben-
zenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide; (16)
N-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexylmethyl}-2-[2-(4-m-
ethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide;
(17)
N-[4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]-2-[2-(4-methoxy-
-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-l-yl]-acetamide;
(18)
N-[4-(1-dimethylamino-3-phenyl-propyl)-cyclohexylmethyl]-2-[2-(4-methoxy--
benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide;
(19)
N-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexylmethyl}-2-[2-(4-m-
ethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide;
(20)
N-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexylmethyl}-2-[2-
-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamid-
e; (21)
N-[4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexylmethyl]-2-[2-(-
4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide;
(22)
N-(2-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-ethyl)--
2-[2-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acet-
amide; (23)
N-(2-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)-2-[2--
(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide-
; (24)
N-(2-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)-
-2-[2-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-l-yl]-ace-
tamide; (25)
N-{2-[4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexyl]-ethyl}-2-[2-(4-m-
ethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide;
(26)
2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1
-yl)-N-(4-((dimethylamino)
(3-fluorophenyl)methyl)cyclohexyl)acetamide; (27)
2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-
1-yl)-N-(4-((dimethylamino)
(4-fluorophenyl)methyl)cyclohexyl)acetamide; (28)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-
-yl]-N-{4-[
dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexylmethyl}-acetamide;
(29)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]--
N-[4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]-acetamide;
(30)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-
1-yl] -N- [4-(1-dimethylamino-
3-phenyl-propyl)-cyclohexylmethyl]-acetamide; (31)
2-[2-(3,4-dichloro-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-N-{4-[dimethylamino-(4-fluoro-phenyl-
)-methyl]-cyclohexylmethyl}-acetamide; (32)
N-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexylmethyl}1-2-[2-(3,-
4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-l-yl]-acetamide-
; (33)
N-(2-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-ethyl)-
-2-[2-(3,4-dichloro-benzene
sulfonyl)-1,2,3,4-tetrahydro-isoquinolin- 1-yl]-acetamide; (34)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-
1-yl]-N-(2-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)-
-acetamide; (35)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]--
N-(2-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)-acetam-
ide; and salts thereof with a physiologically acceptable acid.
19. A pharmaceutical composition comprising a substituted
sulfonamide compound according to claim 1, and at least one
pharmaceutically acceptable carrier or auxiliary substance.
20. A process for preparing a substituted sulfonamide compound
according to claim 1 corresponding to formula Ia, wherein q
represents 0 and R.sup.1through R.sup.8, R.sup.H, R.sup.J, A, Z, Q,
m, n and p have the respective meanings given in claim 1, said
process comprising reacting a carboxylic acid corresponding to
formula III with a primary or secondary amine corresponding to
formula II ##STR00045## in the presence of a water-removing agent,
and optionally in the presence of HOAt or HOBt and of an organic
base, in an organic solvent.
21. A process according to claim 20, wherein: the water removing
agent is slected from the group consisting of sodium sulfate,
magnesium sulfate, phosphorus oxide, CDI, DCC optionally bonded to
a polymer, TBTU, EDCI, PyBOP and PFPTFA; the organic base is DIPEA
or pyridine, or the organic solvent is selected from the group
consisting of THF, dichloromethane, diethyl ether, dioxane, DMF or
acetonitrile.
22. A method of treating or inhibiting pain in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a substituted sulfonamide compound according to
claim 1.
23. A method according to claim 22, wherein said pain is selected
from the group consisting of acute pain, visceral pain, neuropathic
pain, chronic pain and inflammatory pain.
24. A method of treating chronic inflammations in a subject, said
method comprising administering to said subject a pharmaceutically
effective amount of a substituted sulfonamide compound according to
claim 1.
Description
BACKGROUND OF THE INVENTION
The present invention relates to substituted sulfonamide
derivatives, to a process for their preparation, to medicaments
comprising these compounds, and to the use of substituted
sulfonamide derivatives in the preparation of medicaments and in
the treatment of pain and various other conditions.
Unlike the constitutive expression of the bradykinin 2 receptor
(B2R), the bradykinin 1 receptor (B1R) is not expressed or is
expressed only weakly in most tissues. However, the expression of
B1R in various cells is inducible. For example, following
inflammation reactions there is a rapid and pronounced induction of
B1R in neuronal cells but also in various peripheral cells such as
fibroblasts, endothelial cells, granulocytes, macrophages and
lymphocytes. Accordingly, in the course of inflammation reactions
there is a switch from B2R to B1R dominance in the cells that are
involved. The cytokines interleukin-1 (IL-1) and tumor necrosis
factor alpha (TNF.alpha.) play a substantial part in this B1R
up-regulation (Passos et al., J. Immunol. 2004, 172, 1839-1847).
Following activation with specific ligands, B1R-expressing cells
are then themselves able to secrete inflammation-promoting
cytokines such as IL-6 and IL-8 (Hayashi et al., Eur. Respir. J.
2000, 16, 452-458). This results in the immigration of further
inflammatory cells, for example neutrophilic granulocytes (Pesquero
et al., PNAS 2000, 97, 8140-8145). By way of these mechanisms, the
bradykinin B1R system can contribute to the chronification of
diseases. This is proved by a large number of animal experiments
(overviews in Leeb-Lundberg et al., Pharmacol. Rev. 2005, 57, 27-77
and Pesquero et al., Biol. Chem. 2006, 387, 119-126). In humans
too, enhanced expression of B1R is found, for example, in
enterocytes and macrophages in the affected tissue of patients with
inflammatory intestinal diseases (Stadnicki et al., Am. J. Physiol.
Gastrointest. Liver Physiol. 2005, 289, G361-366) or on
T-lymphocytes of patients with multiple sclerosis (Prat 1999), or
activation of the bradykinin B2R-B1R system is found following
infections with Staphylococcus aureus (Bengtson et al., Blood 2006,
108, 2055-2063). Infections with Staphylococcus aureus are
responsible for symptoms ranging from superficial skin infections
to septic shock.
Due to the described pathophysiological relationships there is a
great therapeutic potential for the use of B1R antagonists in acute
and, in particular, chronic inflammatory diseases. These include
respiratory diseases (Asthma bronchiale, allergies,
COPD/chronic-obstructive pulmonary disease, cystic fibrosis, etc.),
inflammatory intestinal diseases (ulcerative colitis, CD/Crohn's
disease, etc.), neurological diseases (multiple sclerosis,
neurodegeneration, etc.), inflammations of the skin (atopic
dermatitis, psoriasis, bacterial infections, etc.) and mucosa
(Behcet's disease, pelvitis, prostatitis, etc.), rheumatic diseases
(rheumatoid arthritis, osteoarthritis, etc.), septic shock and
reperfusion syndrome (following heart attack, stroke).
In addition, the bradykinin (receptor) system is also involved in
regulating angiogenesis (potential as an angiogenesis inhibitor in
cancer and macular degeneration of the eye), and B1R knockout mice
are protected against the induction of excess weight as a result of
a particularly high-fat diet (Pesquero et al., Biol. Chem. 2006,
387, 119-126). B1R antagonists are therefore suitable also for the
treatment of obesity.
B1R antagonists are suitable in particular for the treatment of
pain, in particular inflammatory pain and neuropathic pain (Calixto
et al., Br. J. Pharmacol. 2004, 1-16), in particular diabetic
neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143).
Compounds that bind to the t-opioid receptor are suitable in
particular for the treatment of pain but also for the treatment of
depression, pruritus, lack of drive, diarrhoea and for
anxiolysis.
SUMMARY OF THE INVENTION
An object underlying the invention was to provide novel compounds
which are suitable especially as pharmacological active ingredients
in medicaments, in particular substances having analgesic activity,
which are suitable for pain therapy--in particular also for the
therapy of inflammatory pain and neuropathic pain.
The invention accordingly provides substituted sulfonamide
derivatives of the general formula I
##STR00002## wherein m represents 0, 1 or 2, n represents 0, 1 or
2, p represents 0, 1 or 2, q represents 0 or 1, A represents
CH--NH--, CH--CH.sub.2--NH--, CH--CH.sub.2--CH.sub.2--NH or
CH--CH.sub.2--CH.sub.2--CH.sub.2--NH, wherein individual hydrogen
atoms can also be replaced by C.sub.1-5-alkyl, R.sup.1 and R.sup.2
independently of one another denote H; C.sub.1-6-alkyl, in each
case saturated or unsaturated, branched or unbranched,
unsubstituted or mono- or poly-substituted; or aryl linked via a
C.sub.1-3-alkyl chain and unsubstituted or mono- or
poly-substituted, wherein R.sup.1 and R.sup.2 do not simultaneously
denote H, or R.sup.1 and R.sup.2 together denote
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.8CH.sub.2CH.sub.2 or (CH.sub.2).sub.3-6,
wherein R.sup.8 denotes H; C.sub.1-6-alkyl, in each case saturated
or unsaturated, branched or unbranched, unsubstituted or mono- or
poly-substituted; aryl, heteroaryl, in each case unsubstituted or
mono- or poly-substituted, or aryl or heteroaryl linked via a
C.sub.1-3-alkyl chain and in each case unsubstituted or mono- or
poly-substituted; R.sup.3 represents C.sub.1-8-alkyl, in each case
saturated or unsaturated, branched or unbranched, unsubstituted or
mono- or poly-substituted; aryl or heteroaryl, in each case
unsubstituted or mono- or poly-substituted; or aryl or heteroaryl
linked via a C.sub.1-3-alkyl chain and in each case unsubstituted
or mono- or poly-substituted; R.sup.4 and R.sup.4a independently of
one another represent H, C.sub.1-6-alkyl, in each case saturated or
unsaturated, branched or unbranched, unsubstituted or mono- or
poly-substituted; F; Cl; aryl, in each case unsubstituted or mono-
or poly-substituted; or aryl linked via a C.sub.1-3-alkyl chain and
in each case unsubstituted or mono- or poly-substituted; R.sup.5
and R.sup.5a independently of one another represent H; or
C.sub.1-6-alkyl, in each case saturated or unsaturated, branched or
unbranched, unsubstituted or mono- or poly-substituted; OH,
OC.sub.1-6-alkyl, F, Cl, phenoxy or benzyloxy; Q denotes a single
bond, --CH.sub.2--, --CH.sub.2--CH.sub.2-- or
##STR00003## wherein represents a single bond or a double bond;
R.sup.6 represents H; C.sub.1-6-alkyl, in each case saturated or
unsaturated, branched or unbranched, unsubstituted or mono- or
poly-substituted; C.sub.3-8-cycloalkyl, saturated or unsaturated,
unsubstituted or mono- or poly-substituted; aryl or heteroaryl,
unsubstituted or mono- or poly-substituted; aryl or
C.sub.3-8-cycloalkyl linked via a C.sub.1-3-alkyl chain; or R.sup.6
together with Q and including the adjacent nitrogen forms a four-,
five-, six- or seven-membered carbocyclic ring which can be
saturated or unsaturated and can contain a further hetero atom O, S
or N, to which a further five- or six-membered ring, saturated or
unsaturated, can be fused; wherein in the case of the common ring
closure Q represents
##STR00004## and the ring can be substituted in any position by
phenyl, .dbd.O, OH, OC.sub.1-6-alkyl, F, Cl, CF.sub.3 or
C.sub.1-6-alkyl; and R.sup.7 represents aryl or heteroaryl, in each
case unsubstituted or mono- or poly-substituted; aryl or heteroaryl
linked via a C.sub.1-3-alkyl group and in each case unsubstituted
or mono- or poly-substituted; in the form of the racemate; of the
enantiomers, diastereoisomers, mixtures of the enantiomers or
diastereoisomers or of an individual enantiomer or diastereoisomer;
of the bases and/or salts of physiologically acceptable acids.
The compounds have an affinity for the human B1 receptor. In
addition, they especially have an affinity for the .mu.-opioid
receptor.
When the group A in the compounds of the general formula I
represents CH--NH--, CH--CH.sub.2--NH--, CH--CH.sub.2--CH.sub.2--NH
or CH--CH.sub.2--CH.sub.2--CH.sub.2--NH--, the C-chain end is
always bonded to the ring and the N-chain end is linked to the
carbonyl group.
Within the scope of this invention, the expressions
"C.sub.1-3-alkyl", C.sub.1-6-alkyl" and "C.sub.1-8-alkyl" denote
acyclic saturated or unsaturated hydrocarbon radicals which can be
branched- or straight-chained as well as unsubstituted or mono- or
poly-substituted, having from 1 to 3 carbon atoms or from 1 to 6
carbon atoms or from 1 to 8 carbon atoms, respectively, that is to
say C.sub.1-3-alkanyls, C.sub.2-3-alkenyls and C.sub.2-3-alkynyls
or C.sub.1-6-alkanyls, C.sub.2-6-alkenyls and C.sub.2-6-alkynyls or
C.sub.1-8-alkanyls, C.sub.2-8-alkenyls and C.sub.2-8-alkynyls.
Alkenyls have at least one C--C double bond and alkynyls have at
least one C--C triple bond. Alkyl is advantageously selected from
the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
hexyl, heptyl, octyl, ethylenyl (vinyl), ethynyl, propenyl
(--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C(.dbd.CH.sub.2)--CH.sub.3), propynyl (--CH--C.ident.CH,
--C.ident.C--CH.sub.3), butenyl, butynyl, pentenyl, pentynyl,
hexenyl and hexynyl. Methyl, ethyl and n-propyl are particularly
advantageous.
Within the scope of this invention, the term "aryl" denotes
aromatic hydrocarbons, including phenyls and naphthyls. The aryl
radicals can also be fused with further saturated, (partially)
unsaturated or aromatic ring systems. Each aryl radical can be
unsubstituted or mono- or poly-substituted, wherein the aryl
substituents can be identical or different and can be located at
any desired and possible position of the aryl. Aryl is
advantageously selected from the group comprising phenyl,
1-naphthyl and 2-naphthyl, each of which can be unsubstituted or
mono- or poly-substituted. The phenyl radical is particularly
advantageous.
The term "heteroaryl" denotes a 5-, 6- or 7-membered cyclic
aromatic group containing at least one, optionally also 2, 3, 4 or
5, hetero atom(s), the hetero atoms being identical or different
and the heterocycle being unsubstituted or mono- or
poly-substituted; in the case of substitution on the heterocycle,
the substituents can be identical or different and can be located
at any desired and possible position of the heteroaryl. The
heterocycle can also be part of a bi- or poly-cyclic system.
Preferred hetero atoms are nitrogen, oxygen and sulfur. It is
preferred for the heteroaryl radical to be selected from the group
comprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl,
thienyl (thiophenyl), benzothienyl, benzothiadiazolyl,
benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl,
phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl,
isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl,
indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl,
quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl and
oxadiazolyl, it being possible for bonding to the compounds of the
general structure I to take place via any desired and possible ring
member of the heteroaryl radical. Thienyl, furyl,
benzothiadiazolyl, oxadiazolyl and pyridyl are particularly
preferred.
The expression "aryl or heteroaryl bonded via C.sub.1-3-alkyl"
means, for the purposes of the present invention, that
C.sub.1-3-alkyl and aryl or heteroaryl have the meanings defined
above and the aryl or heteroaryl radical is bonded to the compound
of the general structure I via a C.sub.1-3-alkyl group. Phenyl,
benzyl and phenethyl are particularly advantageous within the scope
of this invention.
In connection with "alkyl" and "cycloalkyl", the term "substituted"
within the scope of this invention is understood as meaning the
substitution of a hydrogen radical by F, Cl, Br, I, --CN, NH.sub.2,
NH--C.sub.1-6-alkyl, NH--C.sub.1-6-alkyl-OH, C.sub.1-6-alkyl,
N(C.sub.1-6-alkyl).sub.2, N(C.sub.1-6-alkyl-OH).sub.2, NO.sub.2,
SH, S--C.sub.1-6-alkyl, S-benzyl, O--C.sub.1-6-alkyl, OH,
O--C.sub.1-6-alkyl-OH, .dbd.O, O-benzyl, C(.dbd.O)C.sub.1-6-alkyl,
CO.sub.2H, CO.sub.2--C.sub.1-6-alkyl, phenyl or benzyl, wherein
polysubstituted radicals are to be understood as being those
radicals that are polysubstituted, for example di- or
tri-substituted, either on different atoms or on the same atom, for
example trisubstituted on the same carbon atom, as in the case of
CF.sub.3 or --CH.sub.2CF.sub.3, or at different positions, as in
the case of --CH(OH)--CH.dbd.CH--CHCl.sub.2. Polysubstitution can
be carried out with the same or with different substituents.
Preferred radicals in connection with "alkyl" and "cycloalkyl" are
F, Cl, --CN, NH.sub.2, OCH.sub.3, OH, CO.sub.2--CH.sub.3,
CO.sub.2--C.sub.2H.sub.5, .dbd.O and SCH.sub.3.
In relation to "aryl" and "heteroaryl", "mono- or poly-substituted"
within the scope of this invention is understood as meaning the
substitution of one or more hydrogen atoms of the ring system one
or more times, for example two, three or four times, by F, Cl, Br,
I, CN, NH.sub.2, NH--C.sub.1-6-alkyl, NH--C.sub.1-6-alkyl-OH,
N(C.sub.1-6-alkyl).sub.2, N(C.sub.1-6-alkyl-OH).sub.2, NO.sub.2,
SH, S--C.sub.1-6-alkyl, OH, O--C.sub.1-6-alkyl,
O--C.sub.1-6-alkyl-OH, C(.dbd.O)C.sub.1-6-alkyl, CO.sub.2H,
CH.sub.2SO.sub.2-phenyl, CO.sub.2--C.sub.1-6-alkyl, OCF.sub.3,
CF.sub.3,
##STR00005## C.sub.1-6-alkyl, phenyl, pyridyl, thienyl or furyl; on
one atom or optionally on different atoms, wherein a substituent
can itself optionally be substituted. The polysubstitution is
carried out with the same substituent or with different
substituents. Preferred substituents for "aryl" are --F, --Cl,
tert-butyl, CF.sub.3, OCF.sub.3,
##STR00006## CH.sub.3 or OCH.sub.3.
Within the scope of this invention, the expression "a salt formed
with a physiologically acceptable acid" is understood as meaning
salts of the active ingredient in question with inorganic or
organic acids that are physiologically acceptable--in particular
when used in humans. The hydrochloride is particularly preferred.
Examples of physiologically acceptable acids are: hydrochloric
acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic
acid, acetic acid, oxalic acid, succinic acid, tartaric acid,
mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid,
glutamic acid,
1,1-dioxo-1,2-dihydro1.lamda..sup.6-benzo[d]isothiazol-3-one
(saccharinic acid), monomethylsebacic acid, 5-oxo-proline,
hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic
acid, 2,4,6-trimethyl-benzoic acid, .alpha.-liponic acid,
acetylglycine, hippuric acid, phosphoric acid and aspartic acid.
Citric acid and hydrochloric acid are particularly preferred.
The expressions (CH.sub.2).sub.3-6 and (CH.sub.2).sub.4-5 are to be
understood as meaning --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
respectively.
Preference is given to substituted amide derivatives of the general
formula I wherein the radicals or groups R.sup.1-R.sup.8, R.sup.H,
R.sup.J, A, Z and Q and also m, n, p and q have the meaning given
above, wherein
"alkyl substituted" and "cycloalkyl substituted" mean the
substitution of one or more hydrogen radicals by F, Cl, Br, I,
--CN, NH.sub.2, NH--C.sub.1-6-alkyl, NH--C.sub.1-6-alkyl-OH,
C.sub.1-6-alkyl, N(C.sub.1-6-alkyl).sub.2,
N(C.sub.1-6-alkyl-OH).sub.2, NO.sub.2, SH, S--C.sub.1-6-alkyl,
S-benzyl, O--C.sub.1-6-alkyl, OH, O--C.sub.1-6-alkyl-OH, .dbd.O,
O-benzyl, C(.dbd.O)C.sub.1-6-alkyl, CO.sub.2H,
CO.sub.2--C.sub.1-6-alkyl, phenyl or benzyl, "aryl substituted" and
"heteroaryl substituted" mean the substitution of one or more
hydrogen atoms of the ring system one or more times, for example
two, three or four times, by F, Cl, Br, I, CN, NH.sub.2,
NH--C.sub.1-6-alkyl, NH--C.sub.1-6-alkyl-OH,
N(C.sub.1-6-alkyl).sub.2, N(C.sub.1-6-alkyl-OH).sub.2, NO.sub.2,
SH, S--C.sub.1-6-alkyl, OH, O--C.sub.1-6-alkyl,
O--C.sub.1-6-alkyl-OH, C(.dbd.O)C.sub.1-6-alkyl, CO.sub.2H,
CH.sub.2SO.sub.2-phenyl, CO.sub.2--C.sub.1-6-alkyl, OCF.sub.3,
CF.sub.3,
##STR00007## C.sub.1-6-alkyl, phenyl, pyridyl, thienyl or furyl, in
the form of the racemate; of the enantiomers, diastereoisomers,
mixtures of the enantiomers or diastereoisomers or of an individual
enantiomer or diastereoisomer; of the bases and/or salts of
physiologically acceptable acids.
The radicals and groups or substituents described hereinafter as
being preferred can be combined in the compounds according to the
invention with the broadest meaning of the other radicals, but also
with preferred meanings of other radicals and groups or
substituents.
Preference is given within the scope of this invention to
substituted sulfonamide derivatives wherein A represents CH--NH--,
CH--CH.sub.2--NH--, CH--CH.sub.2--CH.sub.2--NH or
CH--CH.sub.2--CH.sub.2--CH.sub.2--NH, wherein individual hydrogen
atoms can also be replaced by C.sub.1-5-alkyl.
p preferably represents 1.
Preference is given to compounds in which q represents 0.
Preference is given also to substituted sulfonamide derivatives
wherein R.sup.1 and R.sup.2 independently of one another denote H;
CH.sub.3; C.sub.2H.sub.5; or phenyl linked via a C.sub.1-3-alkyl
chain, wherein R.sup.1 and R.sup.2 do not simultaneously denote H,
or R.sup.1 and R.sup.2 together denote
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2NR.sup.8CH.sub.2CH.sub.2 or (CH.sub.2).sub.3-5.
Particular preference is given to substituted sulfonamide
derivatives wherein R.sup.1 and R.sup.2 independently of one
another denote H or CH.sub.3, in particular CH.sub.3.
Preference is given within the scope of this invention also to
substituted sulfonamide derivatives wherein R.sup.3 represents aryl
or heteroaryl, in each case unsubstituted or mono- or
poly-substituted; or aryl linked via a C.sub.1-3-alkyl chain and in
each case unsubstituted or mono- or poly-substituted.
Particular preference is given to substituted sulfonamide
derivatives wherein R.sup.3 represents 2-thienyl, 4-fluorophenyl,
3-fluorophenyl, 4-chlorophenyl, phenethyl, phenyl or benzyl.
Preference is given also to substituted sulfonamide derivatives
wherein R.sup.4 and R.sup.4a each represent H.
In addition, preference is given to substituted sulfonamide
derivatives wherein R.sup.5 and R.sup.5a each represent H.
Preference is given also to substituted sulfonamide derivatives
wherein R.sup.6 represents methyl, ethyl or benzyl and Q represents
a single bond, wherein R.sup.6 in particular represents methyl.
Preference is further given to substituted sulfonamide derivatives
wherein
##STR00008## represents
##STR00009##
Preference is given also to substituted sulfonamide derivatives
wherein Q is
##STR00010##
Preference is given also to substituted sulfonamide derivatives
wherein R.sup.7 represents phenyl or naphthyl, unsubstituted or
mono- or poly-substituted, in particular phenyl.
Particular preference is given to substituted sulfonamide
derivatives wherein R.sup.7 represents 2,4-dichlorophenyl,
2,4,6-trichlorophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl,
2,6-dimethyl-4-methoxyphenyl, 3,4-dichlorophenyl,
2,5-dimethyl-4-chlorophenyl or naphthyl.
Preference is given also to substituted sulfonamide derivatives
wherein the group
##STR00011## of formula I represents
##STR00012## m represents 0, 1 or 2; n represents 0; q represents
0; and R.sup.5 and R.sup.5a represent H; or Q represents a single
bond; m represents 0, 1 or 2; n represents 1 or 2; q represents 0
or 1; R.sup.4 and R.sup.4a each independently of the other
represents H or aryl; R.sup.5 and R.sup.5a represent H; and R.sup.6
represents H or C.sub.1-6-alkyl; or Q represents
##STR00013## m represents 0 or 1, preferably 0; n and q represent
0; R.sup.5 and R.sup.5a represent H; and R.sup.6 represents H or
C.sub.1-6-alkyl.
Preference is given also to substituted sulfonamide derivatives
wherein in the general formula I A represents N, NH--CH,
NH--CH.sub.2--CH or NH--CH.sub.2--CH.sub.2--CH, wherein individual
hydrogen atoms can also be replaced by C.sub.1-5-alkyl; R.sup.1 and
R.sup.2 independently of one another represent C.sub.1-6-alkyl, in
particular methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl and tert-butyl, or together with the nitrogen atom to
which they are bonded form a group selected from
##STR00014## and R.sup.3 represents aryl, in particular phenyl or
furanyl, which can be linked via a C.sub.1-3-alkyl group, wherein
the aryl is in each case unsubstituted or mono- or poly-substituted
by identical or different substituents selected independently from
the group consisting of methyl, ethyl, methoxy, ethoxy, F, Cl, Br,
F, CN, CF.sub.3, OCF.sub.3 and OH.
Preference is further given to substituted sulfonamide derivatives
wherein the group
##STR00015## in formula I represents
##STR00016## m represents 1 or 2, in particular 1; n and q
represent 0; R.sup.5 and R.sup.5a represent H; A represents N,
NH--CH or NH--CH.sub.2--CH, in particular N or NH--CH; R.sup.1 and
R.sup.2 independently of one another represent C.sub.1-6-alkyl, in
particular methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl and tert-butyl, or together with the nitrogen atom to
which they are bonded form a group selected from
##STR00017## and R.sub.3 represents phenyl which can be linked via
a C.sub.1-3-alkyl group, wherein the phenyl is in each case
unsubstituted or mono- or poly-substituted by identical or
different substituents selected independently from the group
consisting of methyl, ethyl, methoxy, ethoxy, F, Cl, Br, F, CN,
CF.sub.3, OCF.sub.3 and OH, in particular methyl, methoxy, F, Cl,
Br, CN, CF.sub.3 and OH.
Very particular preference is given to substituted sulfonamide
compounds selected from the group consisting of: (1)
N-(3-{3-[4-(dimethylaminophenylmethyl)cyclohexyl]ureido}propyl)-4-methoxy-
-2,3,6,N-tetramethylbenzenesulfonamide (2)
(N-(3-(3-((4-((dimethylamino)(phenyl)methyl)cyclohexyl)methyl)ureido)prop-
yl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide (3)
4-methoxy-N,2,3,6-tetramethyl-N-(3-(3-(4-(phenyl(pyrrolidin-1-yl)methyl)c-
yclohexyl)ureido)propyl)benzenesulfonamide (4)
4-(dimethylamino-phenyl-methyl)-piperidine-1-carboxylic acid
{3-[(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-methyl-amino]-propyl}-ami-
de (5)
5-[methyl-(2,4,6-trichloro-benzenesulfonyl)-amino]-pentanecarboxyli-
c acid [4-(dimethylamino-phenyl-methyl)-cyclohexyl]-amide (6)
5-[methyl-(2,4,6-trichloro-benzenesulfonyl)-amino]-pentanecarboxylic
acid [4-(phenyl-piperidin-1-yl-methyl)-cyclohexyl]-amide (7)
5-[methyl-(2,4,6-trichloro-benzenesulfonyl)-amino]-pentanecarboxylic
acid [4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]-amide (8)
N-[4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]-2-[1-(3-trifluoromet-
hylbenzenesulfonyl)-piperidin-2-yl]-acetamide (9)
N-[4-(dimethylamino-phenyl-methyl)-cyclohexyl]-2-[2-(4-methoxy-benzenesul-
fonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide (10)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]--
N-[4-(dimethylamino-phenyl-methyl)-cyclohexyl]-acetamide (11)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-[4-(dimethylamino-pheny-
lmethyl)-cyclohexyl]-benzamide (12)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydrobenzo[b-
]thiophene-3-carboxylic acid
[4-(dimethylamino-phenyl-methyl)cyclohexyl]-amide (13)
N-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexyl}-2-[2-(4-methoxy-
benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide
(14)
N-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexyl}-2-[2-(4-methoxy-
benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide
(15)
N-[4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexyl]-2-[2-(4-methoxybenz-
enesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide (16)
N-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexylmethyl}-2-[2-(4-m-
ethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide
(17)
N-[4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]-2-[2-(4-methoxy-
benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide
(18)
N-[4-(1-dimethylamino-3-phenyl-propyl)-cyclohexylmethyl]-2-[2-(4-methoxyb-
enzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide (19)
N-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexylmethyl}-2-[2-(4-m-
ethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide
(20)
N-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexylmethyl}-2-[2-
-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamid-
e (21)
N-[4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexylmethyl]-2-[2-(4-
-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide
(22)
N-(2-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-ethyl)--
2-[2-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acet-
amide (23)
N-(2-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexyl}-et-
hyl)-2-[2-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-
-acetamide (24)
N-(2-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)-2-[2--
(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide
(25)
N-{2-[4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexyl]-ethyl}-2-[2-
-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamid-
e (26)
2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-y-
l)-N-(4-((dimethylamino)(3-fluorophenyl)methyl)cyclohexyl)acetamide
(27)
2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(-
4-((dimethylamino)(4-fluorophenyl)methyl)cyclohexyl)acetamide (28)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]--
N-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexylmethyl}-acetamide
(29)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-
-yl]-N-[4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]-acetamide
(30)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]--
N-[4-(1-dimethylamino-3-phenyl-propyl)-cyclohexylmethyl]-acetamide
(31)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]--
N-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexylmethyl}-acetamide
(32)
N-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexylmethyl}-2-[2-
-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-aceta-
mide (33)
N-(2-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-eth-
yl)-2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-y-
l]-acetamide (34)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]--
N-(2-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)-acetam-
ide (35)
2-[2-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoli-
n-1-yl]-N-(2-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl-
)-acetamide (36)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-{4-[dimethylamino-(3-fl-
uoro-phenyl)-methyl]-cyclohexyl}-benzamide (37)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-{4-[dimethylamino-(4-fl-
uoro-phenyl)-methyl]-cyclohexyl}-benzamide (38)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-[4-(dimethylamino-pheny-
lmethyl)-cyclohexylmethyl]-benzamide (39)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-[4-(1-dimethylamino-3-p-
henyl-propyl)-cyclohexylmethyl]-benzamide (40)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-{4-[dimethylamino-(4-fl-
uoro-phenyl)-methyl]-cyclohexylmethyl}-benzamide (41)
N-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexylmethyl}-2-[(3,4-d-
ichloro-benzenesulfonyl)-methyl-amino]-benzamide (42)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-[4-(dimethylamino-thiop-
hen-2-yl-methyl)-cyclohexylmethyl]-benzamide (43)
N-(2-{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexyl}-ethyl)-2-[(3-
,4-dichloro-benzenesulfonyl)-methyl-amino]-benzamide (44)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-(2-{4-[dimethylamino-(3-
-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)-benzamide (45)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-N-(2-{4-[dimethylamino-(4-
-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)-benzamide (46)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydrobenzo[b-
]thiophene-3-carboxylic acid
[4-(dimethylamino-phenyl-methyl)cyclohexylmethyl]-amide (47)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydrobenzo[b-
]thiophene-3-carboxylic acid
{4-[dimethylamino-(4-fluoro-phenyl)methyl]-cyclohexylmethyl}-amide
(48)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydrobenzo[b-
]thiophene-3-carboxylic acid
{4-[(4-chloro-phenyl)-dimethylamino-methyl]-cyclohexylmethyl}-amide
(49)
2-[(3,4-dichloro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydrobenzo[b-
]thiophene-3-carboxylic acid
[4-(dimethylamino-thiophen-2-yl-methyl)cyclohexylmethyl]-amide (50)
N-(2-(4-((4-chlorophenyl)(dimethylamino)methyl)cyclohexyl)ethyl)-2-(3,4-d-
ichloro-N-methylphenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-c-
arboxamide (51)
2-(3,4-dichloro-N-methylphenylsulfonamido)-N-(2-(4-((dimethylamino)(3-flu-
orophenyl)methyl)cyclohexyl)ethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-c-
arboxamide (52)
2-(3,4-dichloro-N-methylphenylsulfonamido)-N-(2-(4-((dimethylamino)(4-flu-
orophenyl)methyl)cyclohexyl)ethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-c-
arboxamide (53)
2-(3,4-dichloro-N-methylphenylsulfonamido)-N-(2-(4-((dimethylamino)(thiop-
hen-2-yl)methyl)cyclohexyl)ethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-ca-
rboxamide (54)
2-[1-(3,4-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-
-yl]-N-[4-(morpholin-4-yl-phenyl-methyl)-cyclohexyl]-acetamide (55)
2-[1-(2,4-dichloro-benzenesulfonyl)-3-oxo-piperazin-2-yl]-N-[4-(morpholin-
-4-yl-phenyl-methyl)-cyclohexylmethyl]-acetamide (56)
2-[1-(2,4-dichloro-benzenesulfonyl)-3-oxo-piperazin-2-yl]-N-[4-(1-morphol-
in-4-yl-3-phenyl-propyl)-cyclohexylmethyl]-acetamide (57)
2-[1-(2,4-dichloro-benzenesulfonyl)-3-oxo-piperazin-2-yl]-N-[4-(3-phenyl--
1-pyrrolidin-1-yl-propyl)-cyclohexylmethyl]-acetamide (58)
2-[1-(2,4-dichloro-benzenesulfonyl)-3-oxo-piperazin-2-yl]-N-[4-(phenyl-py-
rrolidin-1-yl-methyl)-cyclohexylmethyl]-acetamide (59)
2-[1-(2,4-dichloro-benzenesulfonyl)-3-oxo-piperazin-2-yl]-N-[4-(3-phenyl--
1-piperidin-1-yl-propyl)-cyclohexyl]-acetamide (60)
2-[1-(2,4-dichloro-benzenesulfonyl)-3-oxo-piperazin-2-yl]-N-[4-(1-morphol-
in-4-yl-3-phenyl-propyl)-cyclohexyl]-acetamide (61)
2-[1-(2,4-dichloro-benzenesulfonyl)-3-oxo-piperazin-2-yl]-N-{4-[(4-methyl-
-piperazin-1-yl)-phenyl-methyl]-cyclohexyl}-acetamide (62)
4-(2,4-dichloro-benzenesulfonyl)-3-{2-[4-(morpholin-4-yl-phenyl-methyl)pi-
peridin-1-yl]-2-oxo-ethyl}-piperazin-2-one (63)
4-(2,4-dichlorophenylsulfonyl)-3-(2-(2-(1-morpholino-2-phenylethyl)piperi-
din-1-yl)-2-oxoethyl)piperazin-2-one (64)
2-[1-(3,4-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-
-yl]-N-[4-(morpholin-4-yl-phenyl-methyl)-cyclohexylmethyl]-acetamide
(65)
2-[1-(3,4-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-
-yl]-N-[4-(1-morpholin-4-yl-3-phenyl-propyl)-cyclohexylmethyl]-acetamide
(66)
2-[1-(3,4-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxa-
lin-2-yl]-N-[4-(3-phenyl-1-pyrrolidin-1-yl-propyl)-cyclohexylmethyl]-aceta-
mide (67)
2-[1-(3,4-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-qui-
noxalin-2-yl]-N-[4-(phenyl-pyrrolidin-1-yl-methyl)-cyclohexylmethyl]-aceta-
mide (68)
2-[1-(3,4-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-qui-
noxalin-2-yl]-N-[4-(3-phenyl-1-piperidin-1-yl-propyl)-cyclohexyl]-acetamid-
e (69)
2-[1-(3,4-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinox-
alin-2-yl]-N-[4-(1-morpholin-4-yl-3-phenyl-propyl)-cyclohexyl]-acetamide
(70)
2-[1-(3,4-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxa-
lin-2-yl]-N-{4-[(4-methyl-piperazin-1-yl)-phenyl-methyl]-cyclohexyl}-aceta-
mide (71)
4-(3,4-dichloro-benzenesulfonyl)-3-{2-[4-(morpholin-4-yl-phenyl--
methyl)piperidin-1-yl]-2-oxo-ethyl}-3,4-dihydro-1H-quinoxalin-2-one
(72)
4-(3,4-dichlorophenylsulfonyl)-3-(2-(4-(1-morpholino-2-phenylethyl)piperi-
din-1-yl)-2-oxoethyl)-3,4-dihydroquinoxalin-2(1H)-one (73)
2-[1-(3,4-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-N-[4-(morpholin-4-yl-
-phenyl-methyl)-cyclohexylmethyl]-acetamide (74)
2-[1-(3,4-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-N-[4-(1-morpholin-4--
yl-3-phenyl-propyl)-cyclohexylmethyl]-acetamide (75)
2-[1-(3,4-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-N-[4-(3-phenyl-1-pyr-
rolidin-1-yl-propyl)-cyclohexylmethyl]-acetamide (76)
2-[1-(3,4-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-N-[4-(phenyl-pyrroli-
din-1-ylmethyl)-cyclohexylmethyl]-acetamide (77)
2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)-N-(4-(3-phenyl-1-(piper-
idin-1-yl)propyl)cyclohexyl)acetamide (78)
2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)-N-(4-(1-morpholino-3-ph-
enylpropyl)cyclohexyl)acetamide (79)
2-[1-(3,4-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-N-{4-[(4-methyl-pipe-
razin-1-yl)-phenyl-methyl]-cyclohexyl}-acetamide (80)
2-[1-(3,4-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-1-[4-(morpholin-4-yl-
-phenylmethyl)-piperidin-1-yl]-ethanone; (81)
2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)-1-(4-(1-morpholino-2-ph-
enylethyl)piperidin-1-yl)ethanone; (82)
2-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-2-yl]-N-[4-(morpholin-4-yl--
phenylmethyl)-cyclohexylmethyl]-acetamide (83)
2-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-2-yl]-N-[4-(1-morpholin-4-y-
l-3-phenyl-propyl)-cyclohexylmethyl]-acetamide (84)
2-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-2-yl]-N-[4-(3-phenyl-1-pyrr-
olidin-1-yl-propyl)-cyclohexylmethyl]-acetamide (85)
2-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-2-yl]-N-[4-(phenyl-pyrrolid-
in-1-ylmethyl)-cyclohexylmethyl]-acetamide (86)
2-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-2-yl]-N-[4-(3-phenyl-1-pipe-
ridin-1-yl-propyl)-cyclohexyl]-acetamide (87)
2-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-2-yl]-N-[4-(1-morpholin-4-y-
l-3-phenyl-propyl)-cyclohexyl]-acetamide (88)
2-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-2-yl]-N-{4-[(4-methyl-piper-
azin-1-yl)-phenyl-methyl]-cyclohexyl}-acetamide (89)
2-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-2-yl]-1-[4-(morpholin-4-yl--
phenylmethyl)-piperidin-1-yl]-ethanone; (90)
2-(1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)-1-(4-(1-morpholino-2-phe-
nylethyl)piperidin-1-yl)ethanone; (91)
1-(3,4-dichlorophenylsulfonyl)-N-(4-((dimethylamino)(phenyl)methyl)cycloh-
exyl)indoline-2-carboxamide (92)
1-(3,4-dichlorophenylsulfonyl)-N-(4-((dimethylamino)(3-fluorophenyl)methy-
l)cyclohexyl)indoline-2-carboxamide (93)
1-(3,4-dichlorophenylsulfonyl)-N-(4-(1-(dimethylamino)-3-phenylpropyl)cyc-
lohexyl)indoline-2-carboxamide (94)
1-(3,4-dichlorophenylsulfonyl)-N-(4-((dimethylamino)(4-fluorophenyl)methy-
l)cyclohexyl)indoline-2-carboxamide (95)
1-(3,4-dichlorophenylsulfonyl)-N-((4-((dimethylamino)(phenyl)methyl)cyclo-
hexyl)methyl)indoline-2-carboxamide (96)
1-(3,4-dichlorophenylsulfonyl)-N-((4-(1-(dimethylamino)-3-phenylpropyl)cy-
clohexyl)methyl)indoline-2-carboxamide (97)
1-(3,4-dichlorophenylsulfonyl)-N-(2-(4-(1-(dimethylamino)-3-phenylpropyl)-
cyclohexyl)ethyl)indoline-2-carboxamide (98)
2-(2-(3,4-dichloro-N-methylphenylsulfonamido)phenyl)-N-(2-(4-((dimethylam-
ino)(phenyl)methyl)cyclohexyl)ethyl)acetamide (99)
2-(2-(3,4-dichloro-N-methylphenylsulfonamido)phenyl)-N-(2-(4-(1-(dimethyl-
amino)-3-phenylpropyl)cyclohexyl)ethyl)acetamide (100)
N-(2-(4-((dimethylamino)(phenyl)methyl)cyclohexyl)ethyl)-1-(4-methoxy-N-m-
ethylphenylsulfonamido)cyclohexanecarboxamide (101)
2-(1-(2,4-dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(4-(morpholino(p-
henyl)methyl)cyclohexyl)acetamide (102)
2-(1-(2,4-dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(4-(phenyl(pyrro-
lidin-1-yl)methyl)cyclohexyl)acetamide (103)
2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl-
)-N-(4-(phenyl(pyrrolidin-1-yl)methyl)cyclohexyl)acetamide (104)
2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)-N-(4-(morpholino(phenyl-
)methyl)cyclohexyl)acetamide (105)
2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)-N-(4-(phenyl(pyrrolidin-
-1-yl)methyl)cyclohexyl)acetamide (106)
2-(1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)-N-(4-(morpholino(phenyl)-
methyl)cyclohexyl)acetamide (107)
2-(1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)-N-(4-(phenyl(pyrrolidin--
1-yl)methyl)cyclohexyl)acetamide (108)
1-(4-((4-methylpiperazin-1-yl)(phenyl)methyl)piperidin-1-yl)-2-(1-(3-(tri-
fluoromethyl)phenylsulfonyl)piperidin-2-yl)ethanone; (109)
1-(4-((4-fluorophenyl)(4-methylpiperazin-1-yl)methyl)piperidin-1-yl)-2-(1-
-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)ethanone; (110)
N-(3-(4-((3-fluorophenyl)(4-methylpiperazin-1-yl)methyl)piperidin-1-yl)-3-
-oxo-1-phenylpropyl)naphthalene-2-sulfonamide (111)
1-(4-(1-(4-methylpiperazin-1-yl)-2-phenylethyl)piperidin-1-yl)-2-(1-(3-(t-
rifluoromethyl)phenylsulfonyl)piperidin-2-yl)ethanone; (112)
1-(4-(1-(4-methylpiperazin-1-yl)-3-phenylpropyl)piperidin-1-yl)-2-(1-(3-(-
trifluoromethyl)phenylsulfonyl)piperidin-2-yl)ethanone; (113)
N-(3-(4-(1-(4-methylpiperazin-1-yl)-3-phenylpropyl)piperidin-1-yl)-3-oxo--
1-phenylpropyl)naphthalene-2-sulfonamide (114)
N-(3-(4-((4-methylpiperazin-1-yl)(phenyl)methyl)piperidin-1-yl)-3-oxo-1-p-
henylpropyl)naphthalene-2-sulfonamide (115)
1-(4-((3-fluorophenyl)(4-methylpiperazin-1-yl)methyl)piperidin-1-yl)-2-(1-
-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)ethanone; (116)
N-(3-(4-(1-(4-methylpiperazin-1-yl)-2-phenylethyl)piperidin-1-yl)-3-oxo-1-
-phenylpropyl)naphthalene-2-sulfonamide (117)
N-(3-(4-((4-fluorophenyl)(4-methylpiperazin-1-yl)methyl)piperidin-1-yl)-3-
-oxo-1-phenylpropyl)naphthalene-2-sulfonamide (118)
3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)-1-(4-(1-(4-meth-
yl-piperazin-1-yl)-2-phenylethyl)piperidin-1-yl)propan-1-one (119)
3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)-1-(4-(1-(4-meth-
yl-piperazin-1-yl)-3-phenylpropyl)piperidin-1-yl)propan-1-one (120)
3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)-1-(4-((3-fluoro-
phenyl)(4-methylpiperazin-1-yl)methyl)piperidin-1-yl)propan-1-one
(121)
3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)-1-(4-((4-fluoro-
phenyl)(4-methylpiperazin-1-yl)methyl)piperidin-1-yl)propan-1-one,
and (122)
3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)-1-(4-((4--
methyl-piperazin-1-yl)(phenyl)methyl)piperidin-1-yl)propan-1-one,
in the form of the racemate; of the enantiomers, diastereoisomers,
mixtures of the enantiomers or diastereoisomers or of an individual
enantiomer or diastereoisomer; of the bases and/or salts of
physiologically acceptable acids.
The invention further provides a process for the preparation of a
substituted sulfonamide derivative according to the invention. In
order to prepare compounds of formula Ia wherein q denotes 0,
amines of the general formula II are reacted with acids of the
general formula III with the addition of a coupling reagent.
##STR00018## In this reaction, the carboxylic acids III are reacted
in an amide formation using primary or secondary amines of the
general formula II in the presence of water-removing agents such as
sodium or magnesium sulfate, phosphorus oxide or reagents such as,
for example, CDI, DCC (optionally polymer-bonded), TBTU, EDCI,
PyBOP or PFPTFA, also in the presence of HOAt or HOBt and of an
organic base, for example DIPEA or pyridine, in an organic solvent
such as THF, dichloromethane, diethyl ether, dioxane, DMF or
acetonitrile, to give the products of the general formula I.
In order to prepare compounds of the general formula Ib wherein q
denotes 1, amines of the general formula II are reacted with
isocyanates or carbamates of formula IV.
##STR00019## In this reaction, carbamates are reacted with amines
of the general formula II in an organic solvent, for example
1,4-dioxane, to give the compounds of the general formula Ib.
Alternatively, the amines of the general formula II are reacted in
an organic solvent with isocyanates of the general formula IV,
optionally in the presence of at least one base, preferably in the
presence of at least one base selected from the group consisting of
triethylamine, 4,4-dimethylaminopyridine and diisopropylethylamine,
to give the compounds of the general formula Ib, which are
optionally purified and/or isolated.
The amine structural units of the general formula II that are used
can be prepared by the following processes, for example. According
to the process designated Process A hereinbelow it is possible to
prepare amine structural units wherein A in the structural unit of
the general formula II represents CHNH.sub.2 or
(CH.sub.2).sub.nNH.sub.2.
##STR00020##
##STR00021##
In this process, ethyl 4-oxocyclohexanecarboxylate or
cyclopentanone-3-carboxylic acid ethyl ester is reacted in an
acetal-forming reaction with a diol derivative in an organic
solvent, such as benzene, toluene or xylene, dichloromethane,
cyclohexane or ethanol, optionally with the addition of catalytic
amounts of p-toluenesulfonic acid, camphorsulfonic acid, pyridinium
tosylate or acetic acid, possibly also in the presence of a
water-removing reagent, such as sulfuric acid, sodium or magnesium
sulfate, molecular sieve or phosphorus oxides, at a temperature of
from RT to the reflux temperature of the organic solvent in
question, to give the acetal A.
The prior esterification of cyclopentanone-3-carboxylic acid to
give cyclopentanone-3-carboxylic acid ethyl ester can be carried
out by reacting cyclopentanone-3-carboxylic acid with ethanol using
sulfuric acid or hydrochloric acid or by reacting
cyclopentanone-3-carboxylic acid with iodoethane using sodium
ethanolate or caesium carbonate in DMF.
The acetal A can be reduced to the aldehyde B in a reduction
reaction with a reducing agent, for example diisobutylaluminium
hydride, sodium aluminium hydride or borane-THF complex, in diethyl
ether, dichloromethane, THF, hexane, toluene or a mixture of the
mentioned solvents, at a temperature of from -95.degree. C. to
-20.degree. C.
The aldehyde B can be converted into the nitrile C by addition of
an amine and a cyanide source. The reaction can take place in one
or two stages. In the two-stage variant, a nitrile alcohol is first
formed and isolated. The formation of the nitrile alcohol can be
carried out by reacting the aldehyde B with HCN, KCN or NaCN.
Suitable solvents are water, methanol, ethanol, THF, piperidine,
diethyl ether or a mixture of these solvents. When NaCN and KCN are
used, the required cyanide is typically liberated by addition of,
for example, sodium hydrogen sulfite, sulfuric acid, acetic acid or
hydrochloric acid. Trimethylsilyl cyanide, for example, is also
suitable as the nitrile source. The liberation of the cyanide can
be effected, for example, by boron trifluoride etherate, InF.sub.3
or HCl. Typical solvents here are water or toluene. An example of a
further suitable cyanide source is (cyano-C)diethylaluminium. THF,
toluene or a mixture of the two solvents can be used as
solvent.
The reaction temperature can be from -78.degree. C. to +25.degree.
C. for all variants. Particularly suitable solvents for the
reaction of the nitrile alcohol with the amine are alcohols, such
as methanol or ethanol. The reaction temperature can be from
0.degree. C. to +25.degree. C. In the single-stage variant, the
nitrile alcohol formed as primary product is formed and reacted
with the amine in situ. In a variant of the reaction procedure, the
aldehyde B is reacted with an amine and 1H-benzotriazole in an
aminal-forming reaction to give the benzotriazole aminal CA. The
benzotriazole aminal can be present in equilibrium in both the 1H
and the 2H form. Suitable solvents include benzene, toluene,
ethanol, diethyl ether or THF. It may be necessary to use a
Dean-Stark water separator, molecular sieve or other water-removing
means. The reaction time is normally from 1 to 20 hours at a
reaction temperature of from +20.degree. C. to +110.degree. C. Both
the nitrile C and the benzotriazole aminal CA can be reacted with
metal organyls, such as magnesium, zinc or lithium organyls, in
organic solvents, for example diethyl ether, dioxane or
tetrahydrofuran, to give aminoacetals D.
The amine ketones E are obtained in an acetal cleavage reaction
under acidic conditions. Suitable acids are both inorganic
Bronstedt or Lewis acids, such as hydrochloric acid, sulfuric acid,
ammonium chloride or hydrogen sulfate, or All.sub.3, as well as
organic acids, such as, for example, p-toluenesulfonic acid, acetic
acid, oxalic acid, trifluoromethanesulfonic acid, formic acid,
trifluoroacetic acid or citric acid. The reaction can be carried
out in various solvents, such as, for example, toluene, THF,
chloroform, DCM, xylene, acetonitrile, water, dioxane, acetone,
diethyl ether or ethyl acetate, at temperatures of from -10.degree.
C. to room temperature. The aldehyde H is obtained from the amine
ketone E in a Wittig reaction using phosphorylides and a strong
base, for example potassium tert-butoxide, n-butyllithium,
s-butyllithium, phenyllithium, lithium diisopropylamide or lithium
hexamethyldisilazide, in organic solvents, such as THF, diethyl
ether, cyclohexane, toluene or a mixture of the solvents, at a
temperature of from -78.degree. C. to +30.degree. C., after acidic
working up of the reaction mixture.
To synthesize the aldehyde K, the Wittig reaction is repeated under
identical conditions using the aldehyde H as starting compound. For
synthesis of structural units in which A represents
(CH.sub.2).sub.nNH.sub.2 wherein n>1, the step is repeated n
times.
The ketone E is reacted in an oxime-forming reaction with
hydroxylamine hydrochloride, sulfate or acetate in an organic
solvent, for example ethanol, methanol, 2-propanol,
2-methyl-propan-2-ol or acetonitrile, with the addition of an
organic base, such as, for example, pyridine, sodium acetate,
triethylamine, 4-dimethylaminopyridine or potassium tert-butoxide,
or of an aqueous solution of an inorganic base, such as sodium
hydrogen carbonate, sodium carbonate, potassium carbonate, sodium
hydroxide or potassium hydroxide, or basic ion exchanger Amberlyst,
to give the oximes F.
The aldehydes H and K can likewise be reacted under the same
conditions to give the oximes I and L, respectively. The amines G
can be obtained by a reduction reaction of the oximes F with a
reducing agent, such as, for example, LiAlH.sub.4, sodium, zinc,
borane-dimethyl sulfide, sodium borohydride/nickel(II) chloride
hexahydrate, in ethanol, methanol, glacial acetic acid, THF,
diethyl ether or dioxane, or by catalytic hydrogenation with
palladium or platinum oxide as heterogeneous catalyst, with the
addition of HCl in an alcohol, such as methanol or ethanol. The
amines J and M can be prepared from the respective oximes I and L
under the same conditions.
Amine structural units of the general formula II wherein A denotes
NH can be prepared by the following process:
##STR00022## Isonipecotic acid methyl ester or
piperidin-4-ylmethanol is subjected to an alkylation reaction.
p-Methoxybenzyl halides are particularly suitable as the alkylating
reagent. The reaction can be carried out in from 1 to 72 hours by
reacting p-methoxybenzyl chloride or bromide in THF, benzene,
toluene, dimethylformamide, acetonitrile, dichloromethane, ethanol
or acetone using a base, such as, for example, triethylamine,
diisopropylethylamine, potassium carbonate or sodium carbonate, at
a temperature of from +20.degree. C. to +80.degree. C.
Alternatively, it is also possible to introduce a BOC group as
protecting group by reaction with di-tert-butyl dicarbonate in an
organic solvent such as THF, dichloromethane, methanol, dioxane,
DMF or diethyl ether, optionally with the use of an inorganic base,
such as sodium carbonate, sodium hydrogen carbonate or sodium
hydroxide, or of an organic base, such as triethylamine,
diisopropylethylamine or n-butyllithium, at a temperature of from
-78.degree. C. to room temperature.
The synthesis steps for reducing the ester N to the aldehyde O,
reaction of the aldehyde O to the aminonitrile P and reaction with
a metal organyl to give the protected amine Q are carried out
analogously to the synthesis steps described for compounds
A.fwdarw.B.fwdarw.C.fwdarw.D.
The protected piperidin-4-ylmethanol can be reacted to give the
aldehyde O by the use of reagents, such as PCC, periodinane, IBX,
TPAP, NMO, MnO.sub.2 or oxalyl chloride, optionally also in the
presence of molecular sieve or of a base, such as triethylamine, in
an organic solvent such as dichloromethane, DMSO, methanol,
ethanol, diethyl ether, THF, DMF, DME, at a temperature of from
-78.degree. C. to the reflux temperature of the organic solvent in
question.
An alternative route for reacting the compounds Q to give the
compound R is carried out analogously to the synthesis steps
described for compounds B.fwdarw.CA.fwdarw.D.
The debenzylation of the compounds Q to give the piperidine
derivative S can be carried out directly with ceric ammonium
nitrate in acetonitrile at room temperature in the course of from
0.5 to 2 hours, or indirectly by reaction of the compound Q with
chloroformic acid benzyl ester in dichloromethane at room
temperature to give the compounds of the general formula R.
Various methods are known for deprotecting the compounds R, for
example in the case of the use of benzyl carbamate protecting
groups, such as, for example, catalytic hydrogenation with Pd or
Pd(OH).sub.2 as catalyst in solvents such as alcohols, preferably
methanol or ethanol, THF, dioxane, ethyl acetate, DMF or mixtures
of the mentioned solvents. Auxiliary reagents such as, for example,
acetic acid, acetic acid chloride, HCl, ammonium acetate, ammonium
formate, water, potassium carbonate, potassium hydroxide,
cyclohexene or 1,4-cyclohexadiene can optionally be added. Also
known is deprotection with the aid of trimethylsilyl iodide in
organic solvents, such as chloroform, dichloromethane or
acetonitrile. It is further possible to use methylsulfonic acid
with the addition of anisole in chloroform or dichloromethane, or
alternatively HCl gas in chloroform or dichloromethane, or HBr in
glacial acetic acid.
BOC protecting groups can be removed by reaction with HCl in
organic solvents, such as dioxane, methanol, ethanol, acetonitrile
or ethyl acetate, or by reaction with trifluoroacetic acid or
methanesulfonic acid in dichloromethane or THF at a temperature of
from 0.degree. C. to 110.degree. C. and with a reaction time of
from 0.5 to 20 hours. The acid structural units used can be
obtained by various methods.
##STR00023## Method A
The amino acids used are esterified using water-removing reagents,
for example inorganic acids such as H.sub.2SO.sub.4 or phosphorus
oxides or organic reagents such as thionyl chloride, in organic
solvents such as THF, diethyl ether, methanol, ethanol or DCM, to
give the amino acid esters, which are then converted into the
sulfonylated amino acid esters in a sulfonylation with sulfonyl
chlorides or bromides or pentafluorophenolates R.sub.3SO.sub.2X
(X=Cl, Br, OPFP), optionally in the presence of an organic or
inorganic base, for example potassium carbonate, sodium hydrogen
carbonate, diisopropylethylamine, triethylamine, pyridine,
diethylamine or DBU, preferably in an organic solvent, for example
acetonitrile, DCM or THF. The sulfonylated amino acid esters react
in an ester cleavage using organic acids, such as trifluoroacetic
acid, or aqueous inorganic acids, such as hydrochloric acid, or
using aqueous inorganic bases such as lithium hydroxide, potassium
hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen
carbonate, potassium carbonate in organic solvents such as
methanol, dioxane, DCM, THF, diethyl ether or these solvents in the
form of mixtures, to give the sulfonylated amino acids.
Method B
The primary amines used are first converted into the sulfonamides
in a sulfonylation reaction with sulfonyl chlorides or bromides or
pentafluorophenolates R.sub.3SO.sub.2X (X Cl, Br, OPFP), optionally
in the presence of an organic or inorganic base, for example
potassium carbonate, sodium hydrogen carbonate,
diisopropylethylamine, triethylamine, pyridine, diethylamine or
DBU, preferably in an organic solvent, for example acetonitrile,
DCM or THF. The sulfonamides are then converted into the
sulfonylated amino acid esters in a second step by an alkylation
reaction with haloalkanes or alcohols in solvents, such as acetone,
DMF, DCM, THF, hexane, toluene, methanol or water, using inorganic
or organic bases, such as potassium carbonate, n-butyllithium,
lithium diisopropylamide, sodium hydride, sodium hydroxide, sodium
methanolate, diisopropylethylamine and triethylamine, and
optionally with the aid of reagents, such as triphenylphosphine,
diisopropyl azodicarboxylate, diethyl azodicarboxylate,
(cyanomethylene)trimethylphosphonate, at a temperature of from
-78.degree. C. to +80.degree. C.
The sulfonylated amino acid esters react in an ester cleavage using
organic acids, such as trifluoroacetic acid, or aqueous inorganic
acids, such as hydrochloric acid, or using aqueous inorganic bases,
such as lithium hydroxide, potassium hydroxide, sodium hydroxide,
sodium carbonate, sodium hydrogen carbonate, potassium carbonate,
in organic solvents such as methanol, dioxane, DCM, THF, diethyl
ether or these solvents in the form of mixtures, to give the
sulfonylated amino acids.
Method C
The amino acids used are converted into the sulfonylated amino
acids in a sulfonylation reaction with sulfonyl chlorides or
bromides or pentafluorophenolates R.sub.3SO.sub.2X (X=Cl, Br,
OPFP), optionally in the presence of an organic or inorganic base,
for example potassium carbonate, sodium hydrogen carbonate,
diisopropylethylamine, triethylamine, pyridine, diethylamine or
DBU, preferably in an organic solvent, for example acetonitrile,
DCM or THF.
Method D
The amino acid esters used are converted into the sulfonylated
amino acid esters in a sulfonylation reaction with sulfonyl
chlorides or bromides or pentafluorophenolates R.sub.3SO.sub.2X
(X=Cl, Br, OPFP), optionally in the presence of an organic or
inorganic base, for example potassium carbonate, sodium hydrogen
carbonate, diisopropylethylamine, triethylamine, pyridine,
diethylamine or DBU, preferably in an organic solvent, for example
acetonitrile, dichloromethane or tetrahydrofuran. The sulfonylated
amino acid esters are then converted into the sulfonylated amino
acid esters in a second step by an alkylation reaction with
haloalkanes or alcohols in solvents, such as acetone, DMF, DCM,
THF, hexane, toluene, methanol or water, using inorganic or organic
bases, such as potassium carbonate, n-butyllithium, lithium
diisopropylamide, sodium hydride, sodium hydroxide, sodium
methanolate, diisopropylethylamine and triethylamine, and
optionally with the aid of reagents, such as triphenylphosphine,
diisopropyl azodicarboxylate, diethyl azodicarboxylate,
(cyanomethylene)trimethylphosphonate, at a temperature of from
-78.degree. C. to +80.degree. C. The sulfonylated amino acid esters
react in an ester cleavage using organic acids, such as
trifluoroacetic acid, or aqueous inorganic acids, such as
hydrochloric acid, or using aqueous inorganic bases, such as
lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium
carbonate, sodium hydrogen carbonate, potassium carbonate, in
organic solvents such as methanol, dioxane, dichloromethane, THF,
diethyl ether or these solvents in the form of mixtures, to give
the sulfonylated amino acids.
Method E
The amino acids used are esterified using water-removing reagents,
for example inorganic acids such as H.sub.2SO.sub.4 or phosphorus
oxides or organic reagents such as thionyl chloride, in organic
solvents such as THF, diethyl ether, methanol, ethanol or DCM, to
give the amino acid esters, which are then reacted in a
sulfonylation with sulfonyl chlorides or bromides or
pentafluorophenolates R.sub.3SO.sub.2X (X=Cl, Br, OPFP), optionally
in the presence of an organic or inorganic base, for example
potassium carbonate, sodium hydrogen carbonate,
diisopropylethylamine, triethylamine, pyridine, diethylamine or
DBU, preferably in an organic solvent, for example acetonitrile,
DCM or THF, to give the sulfonylated amino acid esters. The
sulfonylated amino acid esters are then converted into the
alkylated, sulfonylated amino acid esters by an alkylation reaction
with haloalkanes or alcohols in solvents, such as acetone, DMF,
DCM, THF, hexane, toluene, methanol or water, using inorganic or
organic bases, such as potassium carbonate, n-butyllithium, lithium
diisopropylamide, sodium hydride, sodium hydroxide, sodium
methanolate, diisopropylethylamine and triethylamine, and
optionally with the aid of reagents, such as triphenylphosphine,
diisopropyl azodicarboxylate, diethyl azodicarboxylate,
(cyanomethylene)trimethylphosphonate, at a temperature of from
-78.degree. C. to +80.degree. C. The sulfonylated amino acid esters
react in an ester cleavage using organic acids, such as
trifluoroacetic acid, or aqueous inorganic acids, such as
hydrochloric acid, or using aqueous inorganic bases such as lithium
hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate,
sodium hydrogen carbonate, potassium carbonate in organic solvents
such as methanol, dioxane, DCM, THF, diethyl ether or these
solvents in the form of mixtures, to give the sulfonylated amino
acids.
Method F
The amino acids are first converted into the sulfonylated amino
acids in a sulfonylation reaction with sulfonyl chlorides or
bromides or pentafluorophenolates R.sub.3SO.sub.2X (X=Cl, Br,
OPFP), optionally in the presence of an organic or inorganic base,
for example potassium carbonate, sodium hydrogen carbonate,
diisopropylethylamine, triethylamine, pyridine, diethylamine or
DBU, preferably in an organic solvent, for example acetonitrile,
dichloromethane or tetrahydrofuran. The sulfonylated amino acids
are then converted into the alkylated, sulfonylated amino acid
esters by an alkylation reaction with haloalkanes or alcohols in
solvents, such as acetone, DMF, DCM, THF, hexane, toluene, methanol
or water, using inorganic or organic bases, such as potassium
carbonate, n-butyllithium, lithium diisopropylamide, sodium
hydride, sodium hydroxide, sodium methanolate,
diisopropylethylamine and triethylamine, and optionally with the
aid of reagents, such as triphenylphosphine, diisopropyl
azodicarboxylate, diethyl azodicarboxylate,
(cyanomethylene)trimethylphosphonate, at a temperature of from
-78.degree. C. to +80.degree. C. The sulfonylated amino acid esters
react in an ester cleavage using organic acids, such as
trifluoroacetic acid, or aqueous inorganic acids, such as
hydrochloric acid, or using aqueous inorganic bases, such as
lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium
carbonate, sodium hydrogen carbonate, potassium carbonate, in
organic solvents such as methanol, dioxane, dichloromethane, THF,
diethyl ether or these solvents in the form of mixtures, to give
the sulfonylated amino acids.
If the substituted sulfonamide compounds according to the invention
are obtained after their preparation in the form of a mixture of
their stereoisomers, preferably in the form of their racemates or
other mixtures of their various enantiomers and/or
diastereoisomers, these can be separated and optionally isolated by
conventional processes known to the person skilled in the art.
Examples which may be mentioned include chromatographic separation
processes, in particular liquid chromatography processes under
normal pressure or under elevated pressure, preferably MPLC and
HPLC processes, as well as fractional crystallisation processes. It
is thereby possible to separate from one another in particular
individual enantiomers, for example by means of HPLC on chiral
stationary phase, or diastereoisomeric salts formed by means of
crystallisation with chiral acids, for example (+)-tartaric acid,
(-)-tartaric acid or (+)-10-camphorsulfonic acid.
It has been shown that the substances according to the invention
are B1 receptor antagonists. The compounds are therefore suitable
for the treatment of acute, visceral, chronic or neuropathic pain
and inflammatory pain, but also for the treatment of respiratory
diseases, diabetes, respiratory diseases, inflammatory intestinal
diseases, neurological diseases, inflammations of the skin,
rheumatic diseases, septic shock, reperfusion syndrome, obesity and
as an angiogenesis inhibitor.
The substances according to the invention are suitable as
pharmaceutical active ingredients in medicaments. The invention
accordingly further provides medicaments comprising at least one
substituted sulfonamide derivative according to the invention as
well as, optionally, suitable additives and/or auxiliary substances
and/or optionally further active ingredients.
The medicaments according to the invention optionally comprise, in
addition to at least one substituted sulfonamide derivative
according to the invention, suitable additives and/or auxiliary
substances, that is to say also carriers, fillers, solvents,
diluents, colourings and/or binders, and can be administered as
liquid medicament forms in the form of injection solutions, drops
or juices, or as semi-solid medicament forms in the form of
granules, tablets, pellets, patches, capsules, plasters or
aerosols. The choice of the auxiliary substances etc. and the
amounts thereof to be employed depend on whether the medicament is
to be administered orally, perorally, parenterally, intravenously,
intraperitoneally, intradermally, intramuscularly, intranasally,
buccally, rectally or locally, for example to the skin, the mucous
membranes or into the eyes. Formulations in the form of tablets,
coated tablets, capsules, granules, drops, juices and syrups are
suitable for oral administration, and solutions, suspensions,
readily reconstitutable dry formulations and sprays are suitable
for parenteral, topical and inhalatory administration. Substituted
sulfonamide derivatives according to the invention in a depot, in
dissolved form or in a plaster, optionally with the addition of
agents which promote penetration through the skin, are suitable
formulations for percutaneous administration. Forms of preparation
which can be used orally or percutaneously can release the
substituted sulfonamide derivatives according to the invention in a
delayed manner. In principle, other further active ingredients
known to the person skilled in the art can be added to the
medicaments according to the invention.
The amount of active ingredient to be administered to the patient
varies according to the weight of the patient, the mode of
administration, the indication and the severity of the disease.
From 0.005 to 20 mg/kg, preferably from 0.05 to 5 mg/kg, of at
least one substituted sulfonamide derivative according to the
invention are conventionally administered.
The medicament can comprise a substituted sulfonamide derivative
according to the invention as a pure diastereoisomer and/or
enantiomer, as a racemate or as a non-equimolar or equimolar
mixture of the diastereoisomers and/or enantiomers.
The invention also provides the use of a substituted sulfonamide
derivative according to the invention in the preparation of a
medicament for the treatment of pain, in particular of acute,
visceral, chronic or neuropathic pain and inflammatory pain.
The invention further provides the use of a substituted sulfonamide
derivative according to the invention in the preparation of a
medicament for the treatment of respiratory diseases.
The substituted sulfonamide derivatives of the general formula I
are also suitable for the treatment of depression, urinary
incontinence, diarrhoea, pruritus, alcohol and drug abuse, lack of
drive, migraine, diabetes, inflammatory intestinal diseases,
neurological diseases, inflammations of the skin, rheumatic
diseases, septic shock, reperfusion syndrome, obesity, as an
angiogenesis inhibitor and for anxiolysis.
The invention accordingly also provides the use of a substituted
sulfonamide derivative of the general formula I in the preparation
of a medicament for the treatment of depression, urinary
incontinence, diarrhoea, pruritus, alcohol and drug abuse, lack of
drive, migraine, diabetes, inflammatory intestinal diseases,
neurological diseases, inflammations of the skin, rheumatic
diseases, septic shock, reperfusion syndrome, obesity, as an
angiogenesis inhibitor and for anxiolysis.
EXAMPLES
The following examples which follow are intended to explain the
invention but do not limit the invention. The yields of the
compounds prepared have not been optimized. All the temperatures
are uncorrected.
The term "RT" means room temperature, "conc." means concentrated,
"d" means days, "min" means minutes, "h" means hours, "M" is a
concentration in mol/l, "MeOH" means methanol, "THF" means
tetrahydrofuran, "aq." means aqueous, "sat." means saturated,
"EtOAc" means ethyl acetate, "NaHCO.sub.3 solution" means sodium
hydrogen carbonate solution, "DCM" means dichloromethane,
"CHCl.sub.3" means chloroform, "DMF" means N,N-dimethylformamide,
"Et.sub.2O" means diethyl ether, "Et.sub.3N" means triethylamine,
"Na.sub.2SO.sub.4" means sodium sulfate, "NH.sub.4Cl solution"
means sat. aq. ammonium chloride solution.
The chemicals and solvents employed were obtained commercially from
the conventional suppliers (Acros, Avocado, Aldrich, Bachem, Fluka,
Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or were synthesised
by methods known in the literature. Silica gel 60 (0.040-0.063 mm)
from E. Merck, Darmstadt was employed as the stationary phase for
the column chromatography.
Abbreviations
TBTU=O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate CDI=1,1'-carbonyldiimidazole
DCC=dicyclohexylcarbodiimide
EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
HOAt=1-hydroxy-7-azabenzotriazole DIPEA=N,N-diisopropylamine
HOBt=1-hydroxybenzotriazole
EDCI=N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
PyBOP=benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate PFPTFA=pentafluorophenyltrifluoroacetyl
OPFP=O-pentafluorophenyl DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
AcOH=acetic acid DIBAL-H=diisobutylaluminium hydride EtOH=ethanol
HBt=1H-benzotriazole KtOBu=potassium tert-butoxide LAH=lithium
aluminium hydride PG=protecting group TEA=triethylamine
TFA=trifluoroacetic acid p-TosOH=p-toluenesulfonic acid
The thin-layer chromatography investigations were carried out using
HPTLC precoated plates, silica gel 60 F 254 from E. Merck,
Darmstadt. The mixing ratios of solvents, mobile phases or for
chromatography investigations are always stated in
volume/volume.
TABLE-US-00001 Amine structural units used No. Name A1
4-(dimethylamino-phenyl-methyl)-cyclohexylamine A2
4-[dimethylamino-(4-fluorophenyl)-methyl]-cyclohexylamine A3
4-[dimethylamino-(3-fluorophenyl)-methyl]-cyclohexylamine A4
4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexylamine A5
4-(1-dimethylamino-3-phenyl-propyl)-cyclohexylamine A6
4-(1-morpholin-4-yl-3-phenyl-propyl)-cyclohexylamine A7
4-(3-phenyl-1-piperidin-1-yl-propyl)-cyclohexylamine A8
4-[(4-methyl-piperazin-1-yl)-phenyl-methyl]-cyclohexylamine A9
4-(phenyl-pyrrolidin-1-yl-methyl)-cyclohexylamine A10
4-(phenyl-piperidin-1-yl-methyl)-cyclohexylamine A11
4-(morpholin-4-yl-phenyl-methyl)-cyclohexylamine A12
[(4-aminomethyl-cyclohexyl)-phenyl-methyl]-dimethylamine A13
[(4-aminomethyl-cyclohexyl)-(4-fluorophenyl)-methyl]- dimethylamine
A14 [(4-aminomethyl-cyclohexyl)-(3-fluorophenyl)-methyl]-
dimethylamine A15
[(4-aminomethyl-cyclohexyl)-(4-chlorophenyl)-methyl]- dimethylamine
A16 [(4-aminomethyl-cyclohexyl)-thiophen-2-yl-methyl]-dimethylamine
A17 [1-(4-aminomethyl-cyclohexyl)-3-phenyl-propyl]-dimethylamine
A18 C-[4-(morpholin-4-yl-phenyl-methyl)-cyclohexyl]-methylamine A19
C-[4-(1-morpholin-4-yl-3-phenyl-propyl)-cyclohexyl]-methylamine A20
C-[4-(phenyl-pyrrolidin-1-yl-methyl)-cyclohexyl]-methylamine A21
C-[4-(3-phenyl-1-pyrrolidin-1-yl-propyl)-cyclohexyl]-methylamine
A22 2-[4-(dimethylamino-phenyl-methyl)-cyclohexyl]-ethylamine A23
2-{4-[dimethylamino-(4-fluorophenyl)-methyl]-
cyclohexyl}-ethylamine A24
2-{4-[dimethylamino-(3-fluorophenyl)-methyl]-
cyclohexyl}-ethylamine A25
2-{4-[(4-chlorophenyl)-dimethylamino-methyl]-
cyclohexyl}-ethylamine A26
2-[4-(dimethylamino-thiophen-2-yl-methyl)- cyclohexyl]-ethylamine
A27 {1-[4-(2-amino-ethyl)-cyclohexyl]-3-phenyl-
propyl}-dimethylamine A28
N,N-dimethyl-1-phenyl-1-(piperidin-4-yl)methanamine A29
4-(phenyl-piperidin-4-yl-methyl)-morpholine A30
4-(2-phenyl-1-piperidin-4-yl-ethyl)-morpholine A31
1-((3-fluorophenyl)(piperidin-4-yl)methyl)-4-methylpiperazine A32
1-((4-fluorophenyl)(piperidin-4-yl)methyl)-4-methylpiperazine A33
1-methyl-4-(phenyl(piperidin-4-yl)methyl)piperazine A34
1-methyl-4-(2-phenyl-1-(piperidin-4-yl)ethyl)piperazine A35
1-methyl-4-(3-phenyl-1-(piperidin-4-yl)propyl)piperazine
Synthesis of the Amine Structural Units
##STR00024## a) Synthesis of the Cyclohexanones Used
The ketones were obtained from commercially available
4-oxo-cyclohexanecarboxylic acid ethyl ester in a multi-stage
synthesis. The yields of the prepared compounds are not optimised.
All temperatures are uncorrected.
1,4-Dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester
4-Oxo-cyclohexanecarboxylic acid ethyl ester (52.8 g, 0.31 mol,
Merck, order no. 814249), ethylene glycol (67.4 g, 1.08 mol) and
p-toluenesulfonic acid (0.7 g) in toluene (160 ml) were stirred for
20 h at RT and the reaction solution was poured into diethyl ether
(300 ml) and washed with water, sodium hydrogen carbonate solution
and sodium chloride solution. The solution was dried (sodium
sulfate) and concentrated in vacuo, and the colourless liquid that
remained was processed further without being purified.
Yield: 66.5 g (100%)
.sup.1H-NMR (CDCl.sub.3): 1.24 (t, 3H); 1.53 (m, 2H); 1.76 (m, 4H);
1.92 (m, 2H); 2.31 (m, 1H); 3.91 (s, 4H); 4.11 (q, 2H).
.sup.13C-NMR (CDCl.sub.3): 14.28 (q); 26.32 (t); 33.76 (t); 41.59
(d); 60.14 (t); 64.21 (t); 107.90 (d); 174.77 (s).
1,4-Dioxa-spiro[4.5]decane-8-carbaldehyde
Diisobutylaluminium hydride (1.5 M solution in toluene, 102 ml, 153
mmol) was added dropwise at -70 to -65.degree. C., under argon, to
a solution of 1,4-dioxa-spiro-[4.5]decane-8-carboxylic acid ethyl
ester (32.13 g, 150 mmol) in abs. toluene (160 ml), and stirring
was carried out for 30 min. The mixture was then quenched at -70 to
-60.degree. C. by addition of methanol (80 ml). The reaction
solution was heated to RT, saturated sodium chloride solution (100
ml) was added, and the reaction solution was filtered off with
suction over kieselguhr. Kieselguhr was washed twice with ethyl
acetate, and the aqueous solution was separated and extracted twice
with ethyl acetate. The combined organic extracts were washed with
saturated sodium chloride solution, dried over sodium sulfate and
concentrated in vacuo.
Yield: 24.01 g (94%), yellow oil
.sup.1H-NMR (CDCl.sub.3): 1.54 (m, 2H); 1.74 (m, 4H); 1.91 (m, 2H);
2.21 (m, 1H); 3.91 (s, 4H); 9.60 (s, 1H).
.sup.13C-NMR (CDCl.sub.3): 23.35 (t); 33.37 (t); 48.18 (d); 64.30
(t); 107.89 (d); 203.51 (s).
Amino-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetonitrile
Dimethylamino-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetonitrile
(R.sup.1=Me, R.sup.2=Me)
40% aqueous dimethylamine solution (85 ml, 0.67 mol),
1,4-dioxa-spiro-[4.5]decane-8-carbaldehyde (240 g, 0.141 mol) and
potassium cyanide (22.05 g, 0.338 mol) were added, while cooling
with ice, to a mixture of 4 N hydrochloric acid (37 ml) and
methanol (22 ml). The mixture was stirred for 4 d at room
temperature; water (80 ml) was added and then the mixture was
extracted with diethyl ether (4.times.100 ml). The organic phase
was dried over sodium sulfate and concentrated in vacuo, and the
product was obtained in the form of a white solid.
Yield: 25.2 g (81%); melting point: 48-51.degree. C.
.sup.1H-NMR (CDCl.sub.3): 1.23-2.03 (m, 9H); 2.28 (s, 6H); 3.16 (d,
1H); 3.93 (m, 4H).
.sup.13C-NMR (CDCl.sub.3): 26.67 (t); 27.93 (t); 33.87 (t); 36.94
(d); 41.90 (q); 64.30 (t); 64.36 (t); 108.33 (d); 115.94 (s).
Morpholino-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetonitrile
(NR.sup.1R.sup.2=morpholine)
KCN (0.17 mol) and morpholine (14.7 g, 0.17 mol) were added to a
solution of 1,4-dioxa-spiro[4.5]decane-8-carboxaldehyde (0.141 mol)
in a mixture of ethanol (141 ml) and water (70 ml), and stirring
was carried out for 72 h at 25.degree. C. After addition of ethyl
acetate (700 ml), the organic phase was separated off and washed in
succession with water (4.times.150 ml) and aqueous FeSO.sub.4
solution (4.times.150 ml). The organic phase was separated off and
dried over Na.sub.2SO.sub.4 and then filtered off. The solvent was
removed in vacuo, and the product was used in the next stage
without being purified further.
Pyrrolidino-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetonitrile
(NR.sup.1R.sup.2=pyrrolidine)
KCN (0.17 mol) and pyrrolidine (12.07 g, 0.17 mol) were added to a
solution of 1,4-dioxa-spiro[4.5]decane-8-carboxaldehyde (0.141 mol)
in a mixture of ethanol (141 ml) and water (70 ml), and stirring
was carried out for 72 h at 25.degree. C. After addition of ethyl
acetate (700 ml), the organic phase was separated off and washed in
succession with water (4.times.150 ml) and aqueous FeSO.sub.4
solution (4.times.150 ml). The organic phase was separated off and
dried over Na.sub.2SO.sub.4 and then filtered off. The solvent was
removed in vacuo, and the product was used in the next stage
without being purified further.
Piperidino-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetonitrile
(NR.sup.1R.sup.2=piperidine)
KCN (0.17 mol) and piperidine (14.45 g, 0.17 mol) were added to a
solution of 1,4-dioxa-spiro[4.5]decane-8-carboxaldehyde (0.141 mol)
in a mixture of ethanol (141 ml) and water (70 ml), and stirring
was carried out for 72 h at 25.degree. C. After addition of ethyl
acetate (700 ml), the organic phase was separated off and washed in
succession with water (4.times.150 ml) and aqueous FeSO.sub.4
solution (4.times.150 ml). The organic phase was separated off and
dried over Na.sub.2SO.sub.4 and then filtered off. The solvent was
removed in vacuo, and the product was used in the next stage
without being purified further.
[(1,4-Dioxa-spiro[4.5]dec-8-yl)-phenyl-methyl]-dimethyl-amine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenyl)
A solution of the aminonitrile (23.56 g, 105 mmol) in abs. THF (100
ml) was added dropwise, under argon and while cooling with ice, to
a 25% solution of phenylmagnesium chloride (144 ml, 262.5 mmol) in
THF, and stirring was carried out for 20 h at RT. For working up
the reaction mixture, saturated ammonium chloride solution (100 ml)
and water (100 ml) were added, while cooling with ice, and
extraction with diethyl ether (3.times.100 ml) was carried out. The
organic phase was washed with water and saturated sodium chloride
solution, dried (sodium sulfate) and concentrated.
Yield: 28.9 g (100%).
.sup.13C-NMR (CDCl.sub.3): 27.05; 28.13; 34.48; 34.57; 36.94
(C.sub.8); 41.64 (N(CH.sub.3).sub.2); 64.15; 74.33 (CH); 109.02
(C.sub.5); 126.70 (C.sub.arom); 127.49 (C.sub.arom); 129.12
(C.sub.arom); 136.57 (C.sub.arom).
[(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-fluorophenyl-methyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-fluorophenyl)
A solution of the aminonitrile (19.89 g, 88 mmol) in abs. THF (160
ml) was added dropwise, under argon and while cooling with ice, to
a 1 M solution of 4-fluorophenylmagnesium bromide in THF (220 ml,
220 mmol), and stirring was carried out for 20 h at RT. For working
up the reaction mixture, saturated ammonium chloride solution (100
ml) and water (100 ml) were added, while cooling with ice, and
extraction with diethyl ether (3.times.100 ml) was carried out. The
organic phase was washed with water and saturated sodium chloride
solution, dried (sodium sulfate) and concentrated.
Yield: 31 g (>100%)
.sup.13C-NMR (CDCl.sub.3): 26.68 (t); 28.11 (t); 34.43 (t); 34.55
(t); 37.37 (d); 41.68 (q); 64.12 (t); 73.65 (d); 108.88 (d); 114.23
(d); 114.44 (d); 130.27; 130.35; 132.43; 160.36 (s); 162.78
(s).
[(1,4-Dioxa-spiro[4.5]dec-8-yl)-3-fluorophenyl-methyl]-dimethyl-amine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=3-fluorophenyl)
A solution of the aminonitrile (23.45 g, 104 mmol) in abs. THF (100
ml) was added dropwise, under argon and while cooling with ice, to
a 1 M solution of 3-fluorophenylmagnesium bromide in THF (208 ml,
208 mmol), and stirring was carried out for 20 h at RT. For working
up the reaction mixture, saturated ammonium chloride solution (100
ml) and water (100 ml) were added, while cooling with ice, and
extraction with diethyl ether (3.times.100 ml) was carried out. The
organic phase was washed with water and saturated sodium chloride
solution, dried and concentrated.
Yield: 30.33 g (99%).
.sup.1H-NMR (CDCl.sub.3): 1.12 (m, 1H); 1.26 (m, 1H); 1.46-1.81 (m,
7H); 2.10 (s, 6H); 3.10 (d, 1H); 3.90 (m, 4H); 6.85 (m, 3H); 7.27
(m, 1H).
.sup.13C-NMR (CDCl.sub.3): 26.80 (t); 28.08 (t); 34.48 (t); 34.45
(t); 34.59 (t); 37.26 (d); 41.71 (q); 64.19 (t); 74.04 (t); 108.91
(d); 113.51 (d); 113.71 (d); 115.52 (d); 115.72 (d); 124.83 (d);
128.82 (d); 128.90 (d); 139.66 (s); 161.15 (s); 163.58 (s).
[(4-Chlorophenyl)-(1,4-dioxa-spiro[4.5]dec-8-yl)-methyl]-dimethyl-amine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-chlorophenyl)
A solution of the aminonitrile (22.43 g, 100 mmol) in abs. diethyl
ether (100 ml) was added dropwise, under argon and while cooling
with ice, to a 1 M solution of 4-chlorophenylmagnesium bromide in
diethyl ether (200 ml, 200 mmol), and stirring was carried out for
20 h at RT. For working up the reaction mixture, saturated ammonium
chloride solution (100 ml) and water (100 ml) were added, while
cooling with ice, and extraction with diethyl ether (3.times.100
ml) was carried out. The organic phase was washed with water and
saturated sodium chloride solution, dried and concentrated.
Yield: 30.9 g (100%)
.sup.13C-NMR (CDCl.sub.3): 26.65 (t); 28.11 (t); 34.46 (t); 34.60
(t); 37.28 (d); 41.76 (q); 64.17 (t); 73.80 (d); 108.88 (s); 127.72
(d); 129.53 (d); 132.39 (d); 135.33 (d).
[(1,4-Dioxa-spiro[4.5]dec-8-yl)-thiophen-2-yl-methyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=2-thienyl)
A solution of the aminonitrile (2.24 g, 10 mmol) in abs. THF (10
ml) was added dropwise, under argon and while cooling with ice, to
a 1 M solution of thiophen-2-yl-magnesium bromide in THF (20 ml, 20
mmol), and stirring was carried out for 20 h at RT. For working up
the reaction mixture, saturated ammonium chloride solution (10 ml)
and water (10 ml) were added, while cooling with ice, and
extraction with diethyl ether (3.times.10 ml) was carried out. The
organic phase was washed with water and saturated sodium chloride
solution, dried and concentrated.
Yield: 2.8 g (100%)
.sup.13C-NMR (CDCl.sub.3): 27.72 (t); 27.88 (t); 34.27 (t); 39.28
(d); 41.10 (q); 64.11 (t); 68.89 (d); 108.88 (s); 123.55 (d);
125.88 (d); 127.53 (d); 139.50 (s).
[1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-3-phenyl-propyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenethyl)
A solution of the aminonitrile (21.93 g, 97 mmol) in abs. THF (180
ml) was added dropwise, under argon and while cooling with ice, to
a 1 M solution of phenylethyl-magnesium chloride in THF (242 ml,
242 mmol), and stirring was carried out for 20 h at RT. For working
up the reaction mixture, saturated ammonium chloride solution (100
ml) and water (100 ml) were added, while cooling with ice, and
extraction with diethyl ether (3.times.100 ml) was carried out. The
organic phase was washed with water and saturated sodium chloride
solution, dried and concentrated.
Yield: 34 g (>100%).
.sup.13C-NMR (CDCl.sub.3): 27.43 (t); 28.95 (t); 29.42 (t); 34.82
(t); 35.40 (t); 38.76 (d); 41.16 (q); 64.17 (t); 67.41 (d); 108.86
(s); 125.41 (d); 127.66 (d); 128.11 (d); 142.69 (s).
[(1,4-Dioxa-spiro[4.5]dec-8-yl)-phenyl-methyl]-morpholine
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenyl)
A 25% solution of phenylmagnesium chloride (144 ml, 262.5 mmol) in
THF was added dropwise at 0.degree. C., under argon, to a solution
of the aminonitrile (105 mmol) in THF (100 ml), and then stirring
was carried out for a further 20 h at 25.degree. C. After addition
of a saturated aqueous NH.sub.4Cl solution (200 ml), the reaction
mixture was extracted with ethyl acetate (3.times.100 ml). The
combined organic phases were then washed with water and with
saturated aqueous NaCl solution. The organic phase was separated
off and dried over Na.sub.2SO.sub.4 and filtered off. The solvent
was removed in vacuo, and the product was purified by column
chromatography (2-5% methanol/dichloromethane).
[1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-3-phenyl-propyl]-morpholine
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenethyl)
A 1 M solution of phenylethylmagnesium chloride in THF (262 ml, 262
mmol) was added dropwise at 0.degree. C., under argon, to a
solution of the aminonitrile (105 mmol) in THF (100 ml), and then
stirring was carried out for a further 20 h at 25.degree. C. After
addition of a saturated aqueous NH.sub.4Cl solution (200 ml), the
reaction mixture was extracted with ethyl acetate (3.times.100 ml).
The combined organic phases were then washed with water and with
saturated aqueous NaCl solution. The organic phase was separated
off and dried over Na.sub.2SO.sub.4 and filtered off. The solvent
was removed in vacuo, and the product was purified by column
chromatography (2-5% methanol/dichloromethane).
[(1,4-Dioxa-spiro[4.5]dec-8-yl)-phenyl-methyl]-pyrrolidine
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenyl)
A 25% solution of phenylmagnesium chloride (144 ml, 262.5 mmol) in
THF was added dropwise at 0.degree. C., under argon, to a solution
of the aminonitrile (105 mmol) in THF (100 ml), and then stirring
was carried out for a further 20 h at 25.degree. C. After addition
of a saturated aqueous NH.sub.4Cl solution (200 ml), the reaction
mixture was extracted with ethyl acetate (3.times.100 ml). The
combined organic phases were then washed with water and with
saturated aqueous NaCl solution. The organic phase was separated
off and dried over Na.sub.2SO.sub.4 and filtered off. The solvent
was removed in vacuo, and the product was purified by column
chromatography (2-5% methanol/dichloromethane).
[1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-3-phenyl-propyl]-pyrrolidine
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenethyl)
A 1 M solution of phenylethylmagnesium chloride in THF (262 ml, 262
mmol) in THF was added dropwise at 0.degree. C., under argon, to a
solution of the aminonitrile (105 mmol) in THF (100 ml), and then
stirring was carried out for a further 20 h at 25.degree. C. After
addition of a saturated aqueous NH.sub.4Cl solution (200 ml), the
reaction mixture was extracted with ethyl acetate (3.times.100 ml).
The combined organic phases were then washed with water and with
saturated aqueous NaCl solution. The organic phase was separated
off and dried over Na.sub.2SO.sub.4 and filtered off. The solvent
was removed in vacuo, and the product was purified by column
chromatography (2-5% methanol/dichloromethane).
[1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-3-phenyl-propyl]-piperidine
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenethyl)
A 1 M solution of phenylethylmagnesium chloride in THF (262 ml, 262
mmol) in THF was added dropwise at 0.degree. C., under argon, to a
solution of the aminonitrile (105 mmol) in THF (100 ml), and then
stirring was carried out for a further 20 h at 25.degree. C. After
addition of a saturated aqueous NH.sub.4Cl solution (200 ml), the
reaction mixture was extracted with ethyl acetate (3.times.100 ml).
The combined organic phases were then washed with water and with
saturated aqueous NaCl solution. The organic phase was separated
off and dried over Na.sub.2SO.sub.4 and filtered. The solvent was
removed in vacuo, and the product was purified by column
chromatography (2-5% methanol/dichloromethane).
1-[1,4-Dioxaspiro[4.5]dec-8-yl)phenylmethyl]piperidine
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenyl)
A solution of
piperidino-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetonitrile (2.8 g, 10.6
mmol) in absolute tetrahydrofuran (10 ml) was added dropwise, under
argon and while cooling with ice, to a 2 M solution of
phenylmagnesium chloride in tetrahydrofuran (13 ml, 26.4 mmol), and
stirring was carried out for 20 h at room temperature. Saturated
ammonium chloride solution (10 ml) and water (10 ml) were then
added dropwise to the reaction mixture, while cooling with ice, and
the solution was extracted with diethyl ether (3.times.30 ml). The
combined organic phases were washed with water (30 ml) and
saturated ammonium chloride solution (30 ml), dried over sodium
sulfate and concentrated in vacuo.
Yield: 3.20 g (96%), yellow, tacky solid
Melting point: could not be determined
.sup.1H-NMR (DMSO-d.sub.6): 0.08-2.30 (m, 19H); 3.12 (d, 1H, J=9.9
Hz); 3.81 (s, 4H); 7.00-7.80 (m, 5H).
4-(Dimethylamino-phenyl-methyl)-cyclohexanone (R.sup.1=Me,
R.sup.2=Me, R.sup.3=phenyl)
The ketal (28.9 g, 0.105 mol) was dissolved in water (44 ml); conc.
hydrochloric acid (64 ml) was added thereto, and stirring was
carried out for 20 h at RT. The reaction mixture was extracted by
shaking with diethyl ether (2.times.100 ml), and the aqueous phase
was rendered alkaline with 5N NaOH, while cooling with ice,
extracted with DCM (3.times.100 ml), dried and concentrated. The
ketone was isolated in the form of a colourless oil.
Yield: 18.2 g (75%)
.sup.1H-NMR (CDCl.sub.3): 1.20 (1H, m); 1.33 (1H, m); 1.74 (1H, m);
2.17 (6H, s, N(CH.sub.3).sub.2); 2.70 (6H, m); 3.10 (1H, d,
C.sub.8--H); 7.07 (2H, m, C.sub.arom--H); 7.23 (3H, m,
C.sub.arom--H).
.sup.13C-NMR (CDCl.sub.3): 29.13; 30.56; 36.90 (C.sub.4); 40.61;
40.82; 41.89 (N(CH.sub.3).sub.2); 73.79 (CH); 127.05 (C.sub.arom);
127.67 (C.sub.arom); 129.00 (C.sub.arom); 136.13 (C.sub.arom);
211.79 (C.dbd.O).
4-[Dimethylamino-(4-fluorophenyl)-methyl]-cyclohexanone
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-fluorophenyl)
The crude product of the ketal (26 g, 88 mmol) was dissolved in
water (40 ml); conc. hydrochloric acid (59 ml) was added thereto,
and stirring was carried out for 20 h at RT. The reaction mixture
was extracted with diethyl ether (2.times.100 ml), and the aqueous
phase was rendered alkaline with 5N NaOH, while cooling with ice,
extracted with DCM (3.times.100 ml), dried and concentrated.
Yield: 21.36 g (98%)
.sup.13C-NMR (CDCl.sub.3): 28.90 (t); 30.48 (t); 37.00 (t); 40.49
(t); 40.72 (t); 41.79 (q); 72.98 (d); 114.42 (d); 114.62 (d);
130.20 (d); 130.28 (d); 131.88 (s); 160.50 (s); 162.93 (s); 211.44
(s).
4-[Dimethylamino-(3-fluorophenyl)-methyl]-cyclohexanone
(R.sup.1=Me, R.sup.2=Me, R.sup.3=3-fluorophenyl)
The ketal (30.3 g, 103 mmol) was dissolved in water (44 ml); conc.
hydrochloric acid (64 ml) was added thereto, and stirring was
carried out for 20 h at RT. The reaction mixture was extracted by
shaking with diethyl ether (2.times.100 ml), and the aqueous phase
was rendered alkaline with 5N NaOH, while cooling with ice,
extracted with DCM (3.times.100 ml), dried and concentrated. The
ketone was isolated in the form of a colourless oil.
Yield: 22.4 g (87%); melting point: 72-75.degree. C.
.sup.13C-NMR (CDCl.sub.3): 28.97 (t); 30.44 (t); 36.90 (t); 40.52
(t); 40.75 (t); 41.82 (q); 73.37 (d); 113.84; 114.06; 115.42;
115.62; 124.71; 129.03; 129.11; 139.00; 139.06; 161.16; 163.60;
211.40 (s).
4-[(4-Chloro-phenyl)-dimethylamino-methyl]-cyclohexanone
(R.sup.3=4-chloro-phenyl)
The ketal (30.98 g, 100 mmol) was dissolved in water (44 ml); conc.
hydrochloric acid (64 ml) was added thereto, and stirring was
carried out for 20 h at RT. The reaction mixture was extracted by
shaking with diethyl ether (2.times.100 ml), and the aqueous phase
was rendered alkaline with 5N NaOH, while cooling with ice,
extracted with DCM (3.times.100 ml), dried and concentrated. The
ketone was isolated in the form of an oil.
Yield: 21.9 g (82%)
.sup.13C-NMR (CDCl.sub.3): 28.88 (t); 30.45 (t); 36.89 (t); 40.49
(t); 40.74 (t); 41.83 (q); 73.12 (d); 127.87 (d); 130.16 (d);
132.75 (d); 13470 (s); 211.35 (s).
4-(Dimethylamino-thiophen-2-yl-methyl)-cyclohexanone (R.sup.1=Me,
R.sup.2=Me, R.sup.3=2-thienyl)
The ketal (2.80 g, 10 mmol) was dissolved in water (4.4 ml); conc.
hydrochloric acid (6.4 ml) was added thereto, and stirring was
carried out for 20 h at RT. The reaction mixture was extracted by
shaking with diethyl ether (2.times.10 ml), and the aqueous phase
was rendered alkaline with 5N NaOH, while cooling with ice,
extracted with DCM (3.times.10 ml), dried and concentrated. The
ketone was isolated in the form of an oil.
Yield: 1.79 g (75%)
.sup.13C-NMR (CDCl.sub.3): 30.02 (t); 30.18 (t); 38.84 (t); 40.29
(t); 39.28 (d); 41.17 (q); 68.24 (d); 123.88 (d); 126.01 (d);
126.34 (d); 138.77 (d); 211.49 (s).
4-(1-Dimethylamino-3-phenyl-propyl)-cyclohexanone (R.sup.1=Me,
R.sup.2=Me, R.sup.3=phenethyl)
The crude product of the ketal (29.6 g, 97 mmol) was dissolved in
water (44 ml); conc. hydrochloric acid (64 ml) was added thereto,
and stirring was carried out for 20 h at RT. The reaction mixture
was extracted by shaking with diethyl ether (2.times.100 ml), and
the aqueous phase was rendered alkaline with 5N NaOH, while cooling
with ice, extracted with DCM (3.times.100 ml), dried and
concentrated. The ketone was isolated in the form of a colorless
oil.
Yield: 16.9 g (58%)
.sup.13C-NMR (CDCl.sub.3): 29.40 (t); 30.02 (t); 30.97 (t); 35.34
(t); 38.71 (t); 40.79 (t); 41.01 (t); 41.23 (q); 66.65 (d); 125.66
(d); 128.12 (d); 128.19 (d); 142.27 (s); 211.70 (s).
4-(Morpholino(phenyl)methyl)cyclohexanone
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenyl)
Conc. HCl and water (1:1, 88 ml) were slowly added at 0.degree. C.
to the Grignard adduct (105 mmol), and stirring was carried out for
20 h at 25.degree. C. The reaction solution was then extracted with
ethyl acetate (2.times.100 ml). After addition of 5N sodium
hydroxide solution to establish a basic pH value, extraction with
dichloromethane (3.times.100 ml) was carried out. The combined
organic phases were dried over Na.sub.2SO.sub.4 and filtered off.
The solvent was removed in vacuo and the product was used in the
next stage without being purified further.
4-(1-Morpholino-3-phenylpropyl)cyclohexanone
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenethyl)
Conc. HCl and water (1:1, 88 ml) were slowly added at 0.degree. C.
to the Grignard adduct (105 mmol), and stirring was carried out for
20 h at 25.degree. C. The reaction solution was then extracted with
ethyl acetate (2.times.100 ml). After addition of 5N sodium
hydroxide solution to establish a basic pH value, extraction with
dichloromethane (3.times.100 ml) was carried out. The combined
organic phases were dried over Na.sub.2SO.sub.4 and filtered off.
The solvent was removed in vacuo and the product was used in the
next stage without being purified further.
4-(Phenyl(pyrrolidin-1-yl)methyl)cyclohexanone
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenyl)
Conc. HCl and water (1:1, 88 ml) were slowly added at 0.degree. C.
to the Grignard adduct (105 mmol), and stirring was carried out for
20 h at 25.degree. C. The reaction solution was then extracted with
ethyl acetate (2.times.100 ml). After addition of 5N sodium
hydroxide solution to establish a basic pH value, extraction with
dichloromethane (3.times.100 ml) was carried out. The combined
organic phases were dried over Na.sub.2SO.sub.4 and filtered off.
The solvent was removed in vacuo and the product was used in the
next stage without being purified further.
4-(3-Phenyl-1-(pyrrolidin-1-yl)propyl)cyclohexanone
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenethyl)
Conc. HCl and water (1:1, 88 ml) were slowly added at 0.degree. C.
to the Grignard adduct (105 mmol), and stirring was carried out for
20 h at 25.degree. C. The reaction solution was then extracted with
ethyl acetate (2.times.100 ml). After addition of 5N sodium
hydroxide solution to establish a basic pH value, extraction with
dichloromethane (3.times.100 ml) was carried out. The combined
organic phases were dried over Na.sub.2SO.sub.4 and filtered off.
The solvent was removed in vacuo and the product was used in the
next stage without being purified further.
4-(3-Phenyl-1-(piperidin-1-yl)propyl)cyclohexanone
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenethyl)
Conc. HCl and water (1:1, 88 ml) were slowly added at 0.degree. C.
to the Grignard adduct (105 mmol), and stirring was carried out for
20 h at 25.degree. C. The reaction solution was then extracted with
ethyl acetate (2.times.100 ml). After addition of 5N sodium
hydroxide solution to establish a basic pH value, extraction with
dichloromethane (3.times.100 ml) was carried out. The combined
organic phases were dried over Na.sub.2SO.sub.4 and filtered off.
The solvent was removed in vacuo and the product was used in the
next stage without being purified further.
4-(Phenylpiperidin-1-yl-methyl)cyclohexanone
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenyl)
A solution of
1-[1,4-dioxaspiro[4.5]dec-8-yl)phenylmethyl]piperidine (3.10 g, 9.8
mmol) in water (8 ml) and concentrated hydrochloric acid (12 ml)
was stirred for 20 h at room temperature. The reaction mixture was
washed with diethyl ether (2.times.20 ml), and the aqueous phase
was adjusted to pH 12 with 5N sodium hydroxide solution, while
cooling with ice, and extracted with dichloromethane (3.times.40
ml). The combined organic phases were dried over sodium sulfate and
concentrated in vacuo.
Yield: 2.00 g (76%), yellowish solid
Melting point: 88-90.degree. C.
.sup.1H-NMR (DMSO-d.sub.6): 1.00-1.56 (m, 10H); 2.02-2.50 (m, 9H);
3.28 (d, 1H, J=10.7 Hz); 7.14-7.37 (m, 5H).
.sup.13C-NMR (DMSO-d.sub.6): 24.4; 26.09; 29.5; 29.7; 34.5; 49.9
(2C); 72.7; 126.7; 127.6 (2C); 128.8 (2C); 136.4; 211.3. 2C signals
are superimposed with the DMSO signal.
Synthesis of the amino-, aminomethyl- and
aminoethyl-cyclohexyls
The corresponding amines were obtained from the cyclohexanone
derivatives.
##STR00025##
Synthesis of the aminocyclohexanes
The aminocyclohexanes were prepared by two-stage reactions from the
appropriately substituted cyclohexanones with hydroxylamine
hydrochloride and subsequent cleavage with lithium aluminium
hydride.
Synthesis of 4-(dimethylamino-phenyl-methyl)-cyclohexylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenyl) A1
4-(Dimethylamino-phenyl-methyl)-cyclohexanrone oxime (R.sup.1=Me,
R.sup.2=Me, R.sup.3=phenyl)
The ketone (9.25 g, 40 mmol) and hydroxylamine hydrochloride (4.17
g, 60 mmol) were dissolved in abs. ethanol (150 ml); basic ion
exchanger Amberlyst A21 (28 g) was added thereto, and stirring was
carried out overnight at RT. The ion exchanger was filtered off and
washed with ethanol (2.times.50 ml). The solution was concentrated
and the residue was adjusted to pH 11 with 5N NaOH. The aqueous
phase was extracted with ethyl acetate (3.times.50 ml), and the
organic phase was dried over sodium sulfate and concentrated in
vacuo.
Yield: 9.54 g (97%); melting point: 110-115.degree. C. (colourless
crystals)
.sup.13C-NMR (CDCl.sub.3): 23.53; 23.70; 27.87; 29.04; 29.48;
30.70; 31.26; 31.40; 37.89 (C.sub.4); 42.02 (N(CH.sub.3).sub.2);
74.36 (CH); 126.87 (C.sub.arom); 127.56 (C.sub.arom); 129.09
(C.sub.arom); 136.57 (C.sub.arom); 160.12 (C.dbd.N--O).
4-(Dimethylamino-phenyl-methyl)-cyclohexylamine (R.sup.1=Me,
R.sup.2=Me, R.sup.3=phenyl) A1
LiAlH.sub.4 (2.92 g, 77 mmol) was added, under argon, to absolute
THF (400 ml), the mixture was heated to 60.degree. C., and the
oxime (9.5 g, 38.5 mmol), dissolved in THF (90 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (100 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the solution was filtered off over kieselguhr. The filter
residue was washed with THF. The THF was removed in vacuo, and the
residue was adjusted to pH 11 with 5N NaOH and extracted with ethyl
acetate (4.times.40 ml). The organic phase was dried over sodium
sulfate and concentrated by evaporation, and the residue was
purified over a silica gel column (300 g) with
acetonitrile/methanol/0.5 M NH.sub.4Cl (9:1:1).
The individual fractions were dissolved in water and DCM and
rendered alkaline with ammonia, and the aqueous phase was extracted
(twice) with DCM.
Overall yield: 6.33 g (71%), oil
.sup.13C-NMR (CDCl.sub.3): 24.22; 24.80; 28.24; 29.96; 32.39;
32.45; 36.03; 36.58; 36.79; 37.93 (C.sub.4); 41.33; 41.89
(N(CH.sub.3).sub.2); 47.42; 50.85; 71.95; 75.22 (CH); 126.52
(C.sub.arom); 127.29 (C.sub.arom); 127.33 (C.sub.arom); 129.04
(C.sub.arom); 129.11 (C.sub.arom); 136.22 (C.sub.arom); 137.03
(C.sub.arom).
Synthesis of
4-[dimethylamino-(4-fluorophenyl)-methyl]-cyclohexylamine
(R.sup.1=Me, R.sup.2=Me R.sup.3=4-fluorophenyl) A2
4-[Dimethylamino-(4-fluorophenyl)-methyl]-cyclohexanone oxime
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-fluorophenyl)
The ketone (10.68 g, 43 mmol) and hydroxylamine hydrochloride (4.52
g, 65 mmol) were dissolved in abs. ethanol (160 ml); basic ion
exchanger Amberlyst A21 (30 g) was added thereto, and stirring was
carried out overnight at RT. The ion exchanger was filtered off and
washed with ethanol (2.times.50 ml). The solution was concentrated,
the residue was adjusted to pH 11 with 5N NaOH, the aqueous phase
was extracted with ethyl acetate (3.times.50 ml), and the organic
phase was dried over sodium sulfate and concentrated in vacuo.
Yield: 10.49 g (93%)
.sup.13C-NMR (CDCl.sub.3): 23.76; 23.66; 27.69; 28.87; 29.50;
30.73; 31.22; 31.38; 38.06 (C.sub.4); 42.01 (N(CH.sub.3).sub.2);
73.66 (CH); 114.36 (C.sub.arom); 114.57 (C.sub.arom); 130.32
(C.sub.arom); 130.40 (C.sub.arom); 132.40 (C.sub.arom); 160.03
(C.dbd.N--O); 160.49 (C.sub.arom); 162.93 (C.sub.arom).
4-[Dimethylamino-(4-fluorophenyl)-methyl]-cyclohexylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-fluorophenyl) A2
LiAlH.sub.4 (3.04 g, 82 mmol) was added, under argon, to absolute
THF (435 ml), the mixture was heated to 60.degree. C., and the
oxime (10.49 g, 40 mmol), dissolved in THF (90 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (100 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the solution was filtered off over kieselguhr. The filter
residue was washed with THF. The THF was removed in vacuo, and the
residue was adjusted to pH 11 with 5N NaOH and extracted with ethyl
acetate (4.times.50 ml). The organic phase was dried over sodium
sulfate and concentrated by evaporation, and the residue was
purified by flash chromatography with acetonitrile/methanol/0.5M
NH.sub.4Cl (9:1:1).
The individual fractions were dissolved in water and DCM and
rendered alkaline with ammonia, and the aqueous phase was extracted
twice with DCM.
Yield: 6.95 g (70%), oil
.sup.13C-NMR (CDCl.sub.3): 24.01; 24.76; 27.99; 29.92; 32.32;
36.26; 36.51; 36.73; 38.07; 41.26 (C.sub.4); 41.85
(N(CH.sub.3).sub.2); 47.31; 50.81; 71.25; 74.44 (CH); 114.01
(C.sub.arom); 114.08 (C.sub.arom); 130.20 (C.sub.arom); 130.27
(C.sub.arom); 132.02 (C.sub.arom); 132.85 (C.sub.arom); 160.22
(C.sub.arom); 162.64 (C.sub.arom).
Synthesis of
4-[dimethylamino-(3-fluorophenyl)-methyl]-cyclohexylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=3-fluorophenyl) A3
4-[Dimethylamino-(3-fluorophenyl)-methyl]-cyclohexanone oxime
(R.sup.1=Me, R.sup.2=Me, R.sup.3=3-fluorophenyl)
The ketone (10 g, 40 mmol) and hydroxylamine hydrochloride (4.17 g,
60 mmol) were dissolved in abs. ethanol (150 ml); basic ion
exchanger Amberlyst A21 (28 g) was added thereto, and stirring was
carried out overnight at RT. The ion exchanger was filtered off and
washed with ethanol (2.times.50 ml). The solution was concentrated,
the residue was adjusted to pH 11 with 5N NaOH, the aqueous phase
was extracted with ethyl acetate (3.times.50 ml), and the organic
phase was dried over sodium sulfate and concentrated in vacuo.
Yield: 10.05 g (95%)
.sup.13C-NMR (CDCl.sub.3): 23.48; 23.66; 27.69; 28.87; 29.39;
30.61; 31.18; 31.33; 37.91 (C.sub.4); 41.99 (N(CH.sub.3).sub.2);
74.00 (CH); 113.70 (C.sub.arom); 113.90 (C.sub.arom); 115.51
(C.sub.arom); 124.80 (C.sub.arom); 128.90 (C.sub.arom); 128.98
(C.sub.arom); 139.48 (C.sub.arom); 139.54 (C.sub.arom); 159.89
(C.dbd.N--O); 161.13 (C.sub.arom); 163.57 (C.sub.arom).
4-[Dimethylamino-(3-fluorophenyl)-methyl]-cyclohexylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=3-fluorophenyl) A3
LiAlH.sub.4 (2.83 g, 75 mmol) was added, under argon, to absolute
THF (400 ml), the mixture was heated to 60.degree. C., and the
oxime (9.86 g, 37.3 mmol), dissolved in THF (90 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (100 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the solution was filtered off over kieselguhr. The filter
residue was washed with THF. The THF was removed in vacuo, and the
residue was adjusted to pH 11 with 5N NaOH and extracted with ethyl
acetate (4.times.40 ml). The organic phase was dried over sodium
sulfate and concentrated by evaporation, and the residue was
purified over a silica gel column (300 g) with
acetonitrile/methanol/0.5M NH.sub.4Cl (9:1:1).
The individual fractions were dissolved in water and DCM and
rendered alkaline with ammonia, and the aqueous phase was extracted
twice with DCM.
Yield: 6.81 g (73%), oil
.sup.13C-NMR (CDCl.sub.3): 24.08; 24.69; 28.05; 29.84; 32.33;
32.37; 36.10; 36.48; 36.69; 37.95; 41.27 (C.sub.4); 41.85
(N(CH.sub.3).sub.2); 47.32; 50.81; 71.63; 74.81 (CH); 113.29
(C.sub.arom); 115.43 (C.sub.arom); 124.74 (C.sub.arom); 128.58
(C.sub.arom); 139.19 (C.sub.arom); 139.99 (C.sub.arom); 160.97
(C.sub.arom); 163.41 (C.sub.arom).
Synthesis of 4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=2-thiophene) A4
4-(Dimethylamino-thiophen-2-yl-methyl)-cyclohexanone oxime
(R.sup.1=Me, R.sup.2=Me, R.sup.3=2-thiophene)
The ketone (9.49 g, 40 mmol) and hydroxylamine hydrochloride (4.17
g, 60 mmol) were dissolved in abs. ethanol (150 ml); basic ion
exchanger Amberlyst A21 (28 g) was added thereto, and stirring was
carried out overnight at RT. The ion exchanger was filtered off and
washed with ethanol (2.times.50 ml). The solution was concentrated,
the residue was adjusted to pH 11 with 5N NaOH. The aqueous phase
was extracted with ethyl acetate (3.times.50 ml), and the organic
phase was dried over sodium sulfate and concentrated in vacuo.
Yield: 9.21 g (91%)
Melting point: 118-121.degree. C., yellow crystals
4-(Dimethylamino-thiophen-2-yl-methyl)-cyclohexylamine (R.sup.1=Me,
R.sup.2=Me, R.sup.3=2-thiophene) A4
LiAlH.sub.4 (2.73 g, 72 mmol) was added, under argon, to absolute
THF (300 ml), the mixture was heated to 60.degree. C., and the
oxime (9.08 g, 35.9 mmol), dissolved in THF (80 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (80 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the solution was filtered off over kieselguhr. The filter
residue was washed with THF. The THF was removed in vacuo, and the
residue was adjusted to pH 11 with 5N NaOH and extracted with ethyl
acetate (3.times.50 ml). The organic phase was dried over sodium
sulfate and concentrated by evaporation, and the residue was
purified over a silica gel column (300 g) with
acetonitrile/methanol/0.5M NH.sub.4Cl (8:2:1).
The individual fractions were dissolved in water and DCM and
rendered alkaline with ammonia, and the aqueous phase was extracted
twice with DCM.
Overall yield: 5.66 g (66%), oil
.sup.13C-NMR (CDCl.sub.3): 24.81; 24.96; 29.26; 29.76; 32.18;
32.22; 36.46; 36.58; 38.10; 39.99; 40.86; 41.20
(N(CH.sub.3).sub.2); 47.66; 50.80; 64.27; 69.82; 123.43; 125.71;
125.75; 125.95; 126.07; 139.34; 139.79.
Synthesis of 4-(1-dimethylamino-3-phenyl-propyl)-cyclohexylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenethyl) A5
4-(1-Dimethylamino-3-phenyl-propyl)-cyclohexanone oxime
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenethyl)
The ketone (10.2 g, 40 mmol) and hydroxylamine hydrochloride (4.17
g, 60 mmol) were dissolved in abs. ethanol (150 ml); basic ion
exchanger Amberlyst A21 (28 g) was added thereto, and stirring was
carried out overnight at RT. The ion exchanger was filtered off and
washed with ethanol (2.times.50 ml), the solution was concentrated,
and the residue was adjusted to pH 11 with 5N NaOH. The aqueous
phase was extracted with ethyl acetate (3.times.50 ml), and the
organic phase was dried over sodium sulfate and concentrated in
vacuo.
Yield: 10.8 g (100%), oil
.sup.13C-NMR (CDCl.sub.3): 23.80; 23.96; 28.80; 29.27; 30.00;
31.21; 31.49; 31.58; 35.89 (C.sub.4); 39.29; 41.26
(N(CH.sub.3).sub.2); 67.24 (CH); 125.58 (C.sub.arom); 128.13
(C.sub.arom); 142.40 (C.sub.arom); 159.99; 160.04 (C.dbd.N--O).
4-(1-Dimethylamino-3-phenyl-propyl)-cyclohexylamine (R.sup.1=Me,
R.sup.2=Me, R.sup.3=phenethyl) A5
LiAlH.sub.4 (3.04 g, 82 mmol) was added, under argon, to absolute
THF (435 ml), the mixture was heated to 60.degree. C., and the
oxime (11.14 g, 40 mmol), dissolved in THF (90 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (100 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the solution was filtered off over kieselguhr. The filter
residue was washed with THF. The THF was removed in vacuo, and the
residue was adjusted to pH 11 with 5N NaOH and extracted with ethyl
acetate (4.times.50 ml). The organic phase was dried over sodium
sulfate and concentrated by evaporation, and the residue was
purified over a silica gel column (300 g) with
acetonitrile/methanol/0.5M NH.sub.4Cl (9:1:1) and (9:4:1).
The individual fractions were dissolved in water and DCM and
rendered alkaline with ammonia, and the aqueous phase was extracted
twice with DCM.
Yield: 5.02 g (50%), oil
.sup.13C-NMR (CDCl.sub.3): 24.70; 25.36; 29.22; 29.35; 30.42;
32.98; 35.46; 35.72; 36.95; 37.07; 38.89 (C.sub.4); 39.32; 41.04;
41.26 (N(CH.sub.3).sub.2); 46.98; 50.85; 66.01; 68.05 (CH); 125.49
(C.sub.arom); 128.11 (C.sub.arom); 128.14 (C.sub.arom); 142.75
(C.sub.arom).
Synthesis of 4-(1-morpholin-4-yl-3-phenyl-propyl)-cyclohexylamine
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenethyl) A6
4-(1-Morpholino-3-phenylpropyl)cyclohexanone oxime
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenethyl)
Amberlyst A21 (40 g) was added to a solution of the ketone (40
mmol) and hydroxylamine hydrochloride (4.17 g, 60 mmol) in absolute
ethanol (200 ml), and stirring was carried out for 20 h at
25.degree. C. After filtration and washing with ethanol
(2.times.200 ml), the solvent was removed in vacuo. The product was
used in the next stage without being purified further.
4-(1-Morpholin-4-yl-3-phenyl-propyl)-cyclohexylamine
(NR.sup.1R.sup.2=morpholine, R.sup.3 phenethyl) A6
The oxime (38.5 mmol) in THF (90 ml) was added dropwise at
60.degree. C. to a reaction mixture of lithium aluminium hydride
(77 mmol) in absolute THF (400 ml), and stirring was carried out
for 4 h at 60.degree. C. Water (100 ml) was then added slowly at
10.degree. C., and the reaction mixture was filtered off over
silica. The filter residue was washed with ethyl acetate, and the
solvent of the combined organic phases was removed in vacuo. The
product was purified by column chromatography (5-10%
methanol/dichloromethane).
Synthesis of 4-(3-phenyl-1-piperidin-1-yl-propyl)-cyclohexylamine
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenethyl) A7
4-(3-Phenyl-1-(piperidin-1-yl)propyl)cyclohexanone oxime
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenethyl)
Amberlyst A21 (40 g) was added to a solution of the ketone (40
mmol) and hydroxylamine hydrochloride (4.17 g, 60 mmol) in absolute
ethanol (200 ml), and stirring was carried out for 20 h at
25.degree. C. After filtration and washing with ethanol
(2.times.200 ml), the solvent was removed in vacuo. The product was
used in the next stage without being purified further.
4-(3-Phenyl-1-piperidin-1-yl-propyl)-cyclohexylamine
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenethyl) A7
The oxime (38.5 mmol) in THF (90 ml) was added dropwise at
60.degree. C. to a reaction mixture of lithium aluminium hydride
(77 mmol) in absolute THF (400 ml), and stirring was carried out
for 4 h at 60.degree. C. Water (100 ml) was then added slowly at
10.degree. C., and the reaction mixture was filtered off over
silica. The filter residue was washed with ethyl acetate, and the
solvent of the combined organic phases was removed in vacuo. The
product was purified by column chromatography (5-10%
methanol/dichloromethane).
Synthesis of 4-(phenylpyrrolidin-1-yl-methyl)cyclohexylamine
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenyl) A9
4-(Phenylpyrrolidin-1-yl-methyl)cyclohexanone oxime
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenyl)
Basic ion exchanger Amberlyst A21 (4 g) was added to a solution of
4-(phenyl-pyrrolidin-1-yl-methyl)cyclohexanone (1.55 g, 5.7 mmol)
and hydroxylamine hydrochloride (594 mg, 8.55 mmol) in anhydrous
ethanol (30 ml), and stirring was carried out for 3 d at room
temperature. The ion exchanger was filtered off and washed with
ethanol (2.times.5 ml). The filtrate was concentrated in vacuo,
water (5 ml) was added to the residue, the pH was adjusted to 11
with 5 N sodium hydroxide solution, and extraction with ethyl
acetate (3.times.15 ml) was carried out. The combined organic
phases were dried over sodium sulfate and concentrated in
vacuo.
Yield: 1.45 g (93%), white solid; melting point: 49-54.degree.
C.
.sup.1H-NMR (DMSO-d.sub.6): 0.50-0.90 (m, 2H); 1.54-2.48 (m, 14H);
3.02-3.18 (m, 1H); 7.10-7.37 (m, 5H); 10.07 (s, 1H).
4-(Phenylpyrrolidin-1-yl-methyl)cyclohexylamine
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenyl) A9
A solution of (phenylpyrrolidin-1-yl-methyl)cyclohexanone oxime
(1.43 g, 5.25 mmol) in absolute tetrahydrofuran (14 ml) was added
dropwise at 60.degree. C., under argon, to a suspension of lithium
aluminium hydride (398 mg, 10.5 mmol) in absolute tetrahydrofuran
(50 ml), and stirring was carried out for 4.5 h at that
temperature. After cooling, water (2 ml) and 4 N sodium hydroxide
solution (500 .mu.l) were added dropwise. The suspension was
filtered, and the filtrate was dried over sodium sulfate and
concentrated in vacuo.
Yield: 1.19 g (88%), yellow oil
.sup.1H-NMR (DMSO-d.sub.6): 0.40-3.25 (m, 21H); 7.10-7.30 (m,
5H).
.sup.13C-NMR (DMSO-d.sub.6): 21.7; 22.6; 22.7; 24.4; 25.7; 29.6;
32.3; 32.5; 36.2; 36.4; 45.9; 49.9; 50.7; 50.8; 126.4; 126.5;
127.3; 127.4; 128.9; 129.0; 138.7, 139.4.
The product is a cis/trans isomer mixture.
Synthesis of 4-(phenylpiperidin-1-yl-methyl)cyclohexylamine
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenyl) A10
4-(Phenylpiperidin-1-yl-methyl)cyclohexanone oxime
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenyl)
Basic ion exchanger Amberlyst A21 (4.80 g) was added to a solution
of 4-(phenyl-piperidin-1-yl-methyl)cyclohexanone (1.85 g, 6.8 mmol)
and hydroxylamine hydrochloride (709 mg, 10.2 mmol) in anhydrous
ethanol (40 ml), and stirring was carried out for 3 d at room
temperature. The ion exchanger was filtered off and washed with
ethanol (2.times.10 ml). The filtrate was concentrated in vacuo,
water (15 ml) was added to the residue, the pH was adjusted to 11
with 5 N sodium hydroxide solution, and extraction with ethyl
acetate (3.times.25 ml) was carried out. The combined organic
phases were dried over sodium sulfate and concentrated in
vacuo.
Yield: 1.70 g (87%), white solid; melting point: 131-137.degree.
C.
.sup.1H-NMR (DMSO-d.sub.6): 0.70-2.40 (m, 18H); 2.82-3.17 (m, 1H);
3.18 (d, 1H, J=9.8 Hz); 7.10-7.37 (m, 5H); 10.08 and 10.11 (2 s,
1H).
The product is an E/Z isomer mixture.
4-(Phenylpiperidin-1-yl-methyl)cyclohexylamine
(NR.sup.1R.sup.2=piperidine, R.sup.3=phenyl) A10
A solution of 4-(phenylpiperidin-1-yl-methyl)cyclohexanone oxime
(1.60 g, 5.6 mmol) in absolute tetrahydrofuran (20 ml) was added
dropwise at 60.degree. C., under argon, to a suspension of lithium
aluminium hydride (425 mg, 11.2 mmol) in absolute tetrahydrofuran
(50 ml), and stirring was carried out for 4 h at that temperature.
After cooling, water (2 ml) and 4 N sodium hydroxide solution (0.5
ml) were added dropwise. The suspension was filtered, and the
filtrate was dried over sodium sulfate and concentrated in
vacuo.
Yield: 1.50 g (98%), yellowish oil
.sup.1H-NMR (DMSO-d.sub.6): 0.60-2.23 (m, 20H); 2.23-2.42 (m,
0.5H); 2.73-2.84 (m, 0.5H); 3.05 (d, 0.5H, J=10.7 Hz); 3.35 (d,
0.5H, J=10.7 Hz); 3.56-3.63 (m, 1H) 7.00-7.40 (m, 5H).
The product is a cis/trans isomer mixture.
Synthesis of 4-(morpholin-4-yl-phenylmethyl)cyclohexylamine
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenyl) A11
4-(Morpholin-4-yl-phenylmethyl)cyclohexanone oxime
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenyl)
Basic ion exchanger Amberlyst A21 (3.1 g) was added to a solution
of 4-(morpholin-4-yl-phenylmethyl)cyclohexanone (1.20 g, 4.4 mmol)
and hydroxylamine hydrochloride (459 mg, 6.6 mmol) in anhydrous
ethanol (30 ml), and stirring was carried out for 20 h at room
temperature. The ion exchanger was filtered off and washed with
ethanol. The filtrate was concentrated in vacuo, water (10 ml) was
added to the residue, the pH was adjusted to 11 with 5 N sodium
hydroxide solution, and extraction with ethyl acetate (3.times.20
ml) was carried out. The combined organic phases were dried over
sodium sulfate and concentrated in vacuo.
Yield: 1.20 g (95%), white solid
Melting point: 82-87.degree. C.
.sup.1H-NMR (DMSO-d.sub.6): 0.66-2.50 (m, 12H); 2.90-3.14 (m, 1H);
3.18-3.48 (m, 1H); 3.48-3.66 (m, 4H); 7.15-7.38 (m, 5H); 10.09 and
10.11 (2 s, 1H).
The product is an E/Z isomer mixture.
4-(Morpholin-4-yl-phenylmethyl)cyclohexylamine
(NR.sup.1R.sup.2=morpholine, R.sup.3 phenyl) A11
A solution of 4-(morpholin-4-yl-phenylmethyl)cyclohexanone oxime
(1.20 g, 4.16 mmol) in absolute tetrahydrofuran (12 ml) was added
dropwise at 60.degree. C., under argon, to a suspension of lithium
aluminium hydride (316 mg, 8.32 mmol) in absolute tetrahydrofuran
(40 ml), and stirring was carried out for 4 h at that temperature.
After cooling, water (1.5 ml) and 4 N sodium hydroxide solution
(0.4 ml) were added dropwise. The suspension was filtered, and the
filtrate was dried over sodium sulfate and concentrated in
vacuo.
Yield: 1.12 g (98%), yellowish oil
.sup.1H-NMR (DMSO-d.sub.6): 0.60-3.65 (m, 21H); 7.10-7.40 (m,
5H).
The product is a cis/trans isomer mixture.
The 4-methylpiperazine derivative was prepared via the
benzotriazole aminal by the following synthesis route:
##STR00026##
11-(1-(1,4-Dioxa-spiro[4.5]dec-8-yl)(4-methylpiperazin-1-yl)methyl)-1H-ben-
zo[d][1,2,3]triazole
The aldehyde (23.4 mmol), N-methylpiperazine (23.4 mmol) and
1H-benzotriazole (23.4 mmol) were heated for 16 h under reflux in
benzene (60 ml), and the resulting water of reaction was removed by
means of a water separator. The benzene was removed in vacuo, and
the residue was used directly in the next stage.
4-Methyl-[1-(1,4-dioxa-spiro[4.5]dec-8-yl)-3-phenyl-propyl]-piperazine
A solution of the benzotriazole adduct (23.5 mmol) in THF was added
dropwise to a solution of phenylmagnesium chloride (47.1 mmol) in
THF, and stirring was carried out for 16 h at 25.degree. C. The
reaction solution was cooled to 0.degree. C., saturated aqueous
NH.sub.4Cl solution was added, and extraction with ethyl acetate
(2.times.300 ml) was then carried out. The organic phase was washed
with water and saturated aqueous NaCl solution. After drying the
organic phase over Na.sub.2SO.sub.4 and filtration, the solvent was
removed in vacuo. The product was purified by column chromatography
(2-5% methanol/dichloromethane).
4-((4-Methylpiperazin-1-yl)(phenyl)methyl)cyclohexanone
Conc. HCl and water (1:1, 88 ml) were added slowly at 0.degree. C.
to the Grignard adduct (105 mmol), and stirring was carried out for
20 h at 25.degree. C. The reaction solution was then extracted with
ethyl acetate (2.times.100 ml). After addition of 5N sodium
hydroxide solution to establish a basic pH value, extraction with
dichloromethane (3.times.100 ml) was carried out. The combined
organic phases were dried over Na.sub.2SO.sub.4 and filtered off.
The solvent was removed in vacuo, and the product was used in the
next stage without being purified further.
4-((4-Methylpiperazin-1-yl)(phenyl)methyl)cyclohexanone oxime
Amberlyst A21 (40 g) was added to a solution of the ketone (40
mmol) and hydroxylamine hydrochloride (4.17 g, 60 mmol) in absolute
ethanol (200 ml), and stirring was carried out for 20 h at
25.degree. C. After filtration and washing with ethanol
(2.times.200 ml), the solvent was removed in vacuo. The product was
used in the next stage without being purified further.
4-[(4-Methyl-piperazin-1-yl)-phenyl-methyl]-cyclohexylamine A8
The oxime (38.5 mmol) in THF (90 ml) was added dropwise at
60.degree. C. to a reaction mixture of lithium aluminium hydride
(77 mmol) in absolute THF (400 ml), and stirring was carried out
for 4 h at 60.degree. C. Water (100 ml) was then added slowly at
10.degree. C., and the reaction mixture was filtered off over
silica. The filter residue was washed with ethyl acetate, and the
solvent of the combined organic phases was removed in vacuo. The
product was purified by column chromatography (5-10%
methanol/dichloromethane).
Synthesis of the aminomethylcyclohexanes
The aminomethylcyclohexanes were prepared from the appropriately
substituted cyclohexanones by three-stage reactions via the
cyclohexylaldehyde stage by reaction with hydroxylamine
hydrochloride and subsequent cleavage with lithium aluminium
hydride.
4-(Dimethylamino-phenyl-methyl)-cyclohexane-carbaldehyde
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenyl)
(Methoxymethyl)triphenylphosphonium chloride (31.5 g, 0.092 mol)
was suspended in abs. THF (150 ml) under argon; potassium
tert-butoxide (10.38 g, 0.092 mol), dissolved in abs. THF (100 ml),
was added dropwise at 0.degree. C., and stirring was then carried
out for 15 min at 0.degree. C.
The ketone (14.2 g, 0.061 mol), dissolved in abs. THF (100 ml), was
then added dropwise at RT to the above solution, and stirring was
carried out overnight at RT. Hydrolysis was carried out dropwise
with water (50 ml) and 6N HCl (150 ml), while cooling with
ice-water. After one hour's stirring at RT, extraction with diethyl
ether (10.times.50 ml) was carried out, and the aqueous phase was
adjusted to pH 11 with 5N NaOH, extracted by shaking with ethyl
acetate (3.times.50 ml), dried over sodium sulfate and concentrated
in vacuo. The crude product was purified over a silica gel column
(300 g) with ethyl acetate/cyclohexane (1:1).
Yield: 12.2 g (82%)
.sup.13C-NMR (CDCl.sub.3): 24.01; 24.22; 25.90; 26.06; 26.40;
27.33; 28.21; 29.92; 37.00; 38.19 (C.sub.4); 41.51; 41.98;
(N(CH.sub.3).sub.2); 47.45; 50.60; 73.37; 75.24 (CH); 126.72
(C.sub.arom); 126.76 (C.sub.arom); 127.48 (C.sub.arom); 129.13
(C.sub.arom); 136.14 (C.sub.arom); 136.79 (C.sub.arom); 204.22;
205.05 (CHO).
4-(Dimethylamino-phenyl-methyl)-cyclohexane-carbaldehyde oxime
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenyl)
The carbaldehyde (7.36 g, 30 mmol) and hydroxylamine hydrochloride
(3.12 g, 45 mmol) were dissolved in abs. ethanol (100 ml); basic
ion exchanger Amberlyst A21 (21 g) was added thereto, and stirring
was carried out overnight at RT. The ion exchanger was filtered off
and washed with ethanol (2.times.50 ml). The solution was
concentrated, and the residue was adjusted to pH 11 with 5N NaOH.
The aqueous phase was extracted with ethyl acetate (3.times.50 ml),
and the organic phase was dried over sodium sulfate and
concentrated in vacuo.
Yield: 7.81 g (100%)
.sup.13C-NMR (CDCl.sub.3): 25.83; 26.34; 27.10; 27.55; 28.25;
29.41; 30.12; 30.32; 34.20; 36.45; 36.74; 37.00; 38.19 (C.sub.4);
41.37; 41.03; (N(CH.sub.3).sub.2); 72.28; 75.59 (CH); 126.77
(C.sub.arom); 127.50 (C.sub.arom); 129.22 (C.sub.arom); 136.14
(C.sub.arom); 136.94 (C.sub.arom); 137.05 (C.sub.arom); 154.84;
155.55; 156.35.
[(4-Aminomethyl-cyclohexyl)-phenyl-methyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenyl) A12
LiAlH.sub.4 (2.27 g, 60 mmol) was added, under argon, to absolute
THF (300 ml); the mixture was heated to 60.degree. C., and the
oxime (7.81 g, 30 mmol), dissolved in THF (60 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (70 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered off over kieselguhr. The
filter residue was washed with THF. The combined organic phases
were concentrated in vacuo, and the residue was adjusted to pH 11
with 5N NaOH and extracted with ethyl acetate (4.times.40 ml). The
organic phase was dried over sodium sulfate and concentrated.
Yield: 6.4 g (87%), oil
.sup.13C-NMR (CDCl.sub.3): 25.53; 26.03; 26.64; 26.68; 29.06;
30.37; 30.51; 30.67; 30.74; 36.01; 38.83; 38.93; (C.sub.4); 41.50;
41.94; (N(CH.sub.3).sub.2); 72.28; 75.59 (CH); 126.77 (C.sub.arom);
127.50 (C.sub.arom); 129.22 (C.sub.arom); 136.14 (C.sub.arom);
136.94 (C.sub.arom); 137.05 (C.sub.arom); 154.84; 155.55;
156.35.
4-[Dimethylamino-(4-fluorophenyl)-methyl]-cyclohexane-carbaldehyde
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-fluorophenyl)
(Methoxymethyl)triphenylphosphonium chloride (25.7 g, 75 mmol) was
suspended in abs. THF (100 ml) under argon; potassium tert-butoxide
(8.42 g, 75 mmol), dissolved in abs. THF (70 ml), was added
dropwise at 0.degree. C., and stirring was then carried out for 15
min at 0.degree. C.
The ketone (12.44 g, 50 mmol), dissolved in abs. THF (75 ml), was
then added dropwise at RT to the above solution, and stirring was
carried out overnight at RT. Hydrolysis was carried out dropwise
with water (38 ml) and 6N HCl (112 ml), while cooling with
ice-water. After one hour's stirring at RT, extraction with diethyl
ether (10.times.50 ml) was carried out, and the aqueous phase was
adjusted to pH 11 with 5N NaOH, extracted by shaking with ethyl
acetate (3.times.50 ml), dried over sodium sulfate and concentrated
in vacuo. The crude product was purified by flash chromatography
with ethyl acetate/cyclohexane (1:1).
Yield: 9.13 g (70%).
.sup.1H-NMR (DMSO, 600 MHz, selected signals): .delta.=1.97 (s, 3H,
minor diastereoisomer); 1.99 (s, 3H, major diastereoisomer); 3.08
(d, 1H, J=9.06 Hz, major diastereoisomer); 3.14 (d, 1H, J=9.82 Hz,
minor diastereoisomer); 9.53 (s, 1H, major diastereoisomer); 9.56
(s, 1H, minor diastereoisomer).
.sup.13C-NMR (CDCl.sub.3, both diastereoisomers): .delta.=23.97;
24.21; 25.85; 26.02; 26.17; 27.35; 28.00; 29.90; 37.26; 38.34;
41.50; 41.95; 47.36; 50.55; 72.75; 75.84; 114.25; 114.45; 130.33;
130.40; 132.61; 160.41; 162.83; 204.10; 204.93.
4-[Dimethylamino-(4-fluorophenyl)-methyl]-cyclohexanecarbaldehyde
oxime (R.sup.1=Me, R.sup.2=Me, R.sup.3=4-fluorophenyl)
The aldehyde (6.50 g, 25 mmol) and hydroxylamine hydrochloride (2.6
g, 37.5 mmol) were dissolved in abs. ethanol (80 ml); basic ion
exchanger Amberlyst A21 (16.5 g) was added thereto, and stirring
was carried out overnight at RT. The ion exchanger was filtered off
and washed with ethanol (2.times.50 ml). The solution was
concentrated, and the residue was adjusted to pH 11 with 5N NaOH.
The aqueous phase was extracted with ethyl acetate (3.times.50 ml),
and the organic phase was dried over sodium sulfate and
concentrated in vacuo.
Yield: 6.9 g (99%)
[(4-Aminomethyl-cyclohexyl)-(4-fluorophenyl)-methyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-fluorophenyl) A13
LiAlH.sub.4 (1.9 g, 50 mmol) was added, under argon, to absolute
THF (360 ml); the mixture was heated to 60.degree. C., and the
oxime (6.9 g, 25 mmol), dissolved in THF (60 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (93 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered off over kieselguhr. The
filter residue was washed with THF. The combined organic phases
were concentrated in vacuo, and the residue was adjusted to pH 11
with 5N NaOH and extracted three times with ethyl acetate (100 ml
each time). The organic phase was dried over sodium sulfate and
concentrated.
Yield: 5.4 g (82%), oil
.sup.13C-NMR (CDCl.sub.3): 25.25; 25.93; 26.60; 28.75; 30.30;
30.40; 30.67; 36.20; 38.78; 38.93; (C.sub.4); 41.24; 41.43
(N(CH.sub.3).sub.2); 48.71; 70.62; 74.69 (CH); 113.97 (C.sub.arom);
114.04 (C.sub.arom); 130.24 (C.sub.arom); 130.31 (C.sub.arom);
132.94 (C.sub.arom); 160.19; 162.62; (C.sub.arom).
4-[Dimethylamino-(3-fluorophenyl)-methyl]-cyclohexane-carbaldehyde
(R.sup.1=Me, R.sup.2=Me, R.sup.3=3-fluorophenyl)
(Methoxymethyl)triphenylphosphonium chloride (15.42 g, 45 mmol) was
suspended in abs. THF (50 ml) under argon; potassium tert-butoxide
(5.05 g, 45 mmol), dissolved in abs. THF (50 ml), was added
dropwise at 0.degree. C., and stirring was then carried out for 15
min at 0.degree. C.
The ketone (7.48 g, 0.30 mmol), dissolved in abs. THF (50 ml), was
then added dropwise at RT to the above solution, and stirring was
carried out overnight at RT. Hydrolysis was carried out dropwise
with water (25 ml) and 6N HCl (75 ml), while cooling with
ice-water. After one hour's stirring at RT, extraction with diethyl
ether (10.times.50 ml) was carried out, and the aqueous phase was
adjusted to pH 11 with 5N NaOH, extracted with ethyl acetate
(3.times.50 ml), dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography with
ethyl acetate/cyclohexane (1:1). Yield: 6.55 g (83%); melting
point: 40-43.degree. C.
.sup.1H-NMR (DMSO, 600 MHz, selected signals): .delta.=1.99 (s,
3H); 2.01 (s, 3H); 3.10 (d, 1H, J=9.06 Hz); 3.18 (d, 1H, J=9.82
Hz); 9.54 (s, 1H); 9.56 (s, 1H).
.sup.13C-NMR (CDCl.sub.3): 23.93; 24.12; 25.79; 25.95; 26.19;
27.19; 27.99; 29.77; 37.05; 38.16; 41.45; 41.91; 47.30; 50.49;
71.50; 74.78; 113.50; 115.37; 124.78; 128.24; 130.59; 131.24;
131.67; 139.14; 139.76; 160.06; 163.50; 204.01; 204.85.
4-[Dimethylamino-(3-fluorophenyl)-methyl]-cyclohexane-carbaldehyde
oxime (R.sup.1=Me, R.sup.2=Me, R.sup.3=3-fluorophenyl)
The carbaldehyde (6.32 g, 24 mmol) and hydroxylamine hydrochloride
(2.5 g, 36 mmol) were dissolved in abs. ethanol (90 ml); basic ion
exchanger Amberlyst A21 (17 g) was added thereto, and stirring was
carried out for 3.5 h at RT. The ion exchanger was filtered off and
washed with ethanol (2.times.50 ml). The solution was concentrated,
and the residue was adjusted to pH 11 with 5N NaOH. The aqueous
phase was extracted with ethyl acetate (3.times.50 ml), and the
organic phase was dried over sodium sulfate and concentrated in
vacuo.
Yield: 6.68 g (100%)
.sup.13C-NMR (CDCl.sub.3): 25.59; 26.21; 27.38; 28.02; 28.36;
29.27; 29.45; 30.00; 34.14; 35.58; 36.56; 38.19 (C.sub.4); 41.33;
41.99; (N(CH.sub.3).sub.2); 72.02; 75.05; 75.19 (CH); 113.55
(C.sub.arom); 115.62 (C.sub.arom); 124.88 (C.sub.arom); 128.78
(C.sub.arom); 128.86 (C.sub.arom); 139.84 (C.sub.arom); 139.90
(C.sub.arom); 154.38; 155.13; 161.10 (C.sub.arom); 163.54
(C.sub.arom).
[(4-Aminomethyl-cyclohexyl)-(3-fluorophenyl)-methyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=3-fluorophenyl) A14
LiAlH.sub.4 (1.82 g, 48 mmol) was added, under argon, to absolute
THF (300 ml); the mixture was heated to 60.degree. C., and the
oxime (6.68 g, 24 mmol), dissolved in THF (60 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (70 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered over kieselguhr. The filter
residue was washed with THF, the organic phases were combined, the
THF was removed in vacuo, and the residue was adjusted to pH 11
with 5N NaOH and extracted with ethyl acetate (4.times.40 ml). The
organic phase was dried over sodium sulfate and concentrated.
Yield: 5.7 g (90%), oil
.sup.13C-NMR (CDCl.sub.3): 25.38; 25.93; 26.44; 28.89; 30.36;
30.45; 30.65; 36.10; 38.87; (C.sub.4); 41.33; 41.49; 41.93
(N(CH.sub.3).sub.2); 71.05; 75.11 (CH); 113.94 (C.sub.arom); 115.53
(C.sub.arom); 124.86 (C.sub.arom); 128.59 (C.sub.arom); 128.67
(C.sub.arom); 140.14 (C.sub.arom); 141.21 (C.sub.arom); 161.03
(C.sub.arom); 163.46 (C.sub.arom).
4-[(4-Chloro-phenyl)-dimethylamino-methyl]-cyclohexanecarbaldehyde
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-chlorophenyl)
(Methoxymethyl)triphenylphosphonium chloride (68.55 g, 200 mmol)
was suspended in abs. THF (200 ml) under argon; potassium
tert-butoxide (22.44 g, 200 mmol), dissolved in abs. THF (300 ml),
was added dropwise at 0.degree. C., and stirring was then carried
out for 15 min at 0.degree. C.
The ketone (38 g, 143 mmol), dissolved in abs. THF (200 ml), was
then added dropwise at RT to the above solution, and stirring was
carried out overnight at RT. Hydrolysis was carried out dropwise
with water (150 ml) and 6N HCl (450 ml), while cooling with
ice-water. After one hour's stirring at RT, extraction with diethyl
ether (10.times.100 ml) was carried out, and the aqueous phase was
adjusted to pH 11 with 5N NaOH, extracted by shaking with ethyl
acetate (3.times.100 ml), dried over sodium sulfate and
concentrated in vacuo. The crude product was purified over two
silica gel columns (400 g) with ethyl acetate/cyclohexane
(1:1).
Yield: 32.17 g (80%).
.sup.1H-NMR (DMSO, 600 MHz, selected signals): .delta.=1.97 (s,
3H); 1.99 (s, 3H); 3.07 (d, 1H, J=9.07 Hz); 3.14 (d, 1H, J=9.82
Hz); 9.53 (s, 1H, 9.55 (s, 1H). .sup.13C-NMR (CDCl.sub.3):
.delta.=23.92; 24.16; 25.80; 25.97; 26.13; 27.25; 27.90; 29.81;
37.08; 38.19; 41.47; 41.96; 47.29; 50.48; 72.81; 74.54; 127.65;
130.28; 132.40; 134.78; 135.43; 203.98; 204.82.
4-[(4-Chlorophenyl)-dimethylamino-methyl]-cyclohexanecarbaldehyde
oxime (R.sup.1=Me, R.sup.2=Me, R.sup.3=4-chlorophenyl)
The carbaldehyde (7.55 g, 27 mmol) and hydroxylamine hydrochloride
(2.81 g, 40 mmol) were dissolved in abs. ethanol (100 ml); basic
ion exchanger Amberlyst A21 (19 g) was added thereto, and stirring
was carried out for 3.5 h at RT. The ion exchanger was filtered off
and washed with ethanol (2.times.50 ml). The solution was
concentrated, and the residue was adjusted to pH 11 with 5N NaOH.
The aqueous phase was extracted with ethyl acetate (3.times.50 ml),
and the organic phase was dried over sodium sulfate and
concentrated in vacuo.
Yield: 7.57 g (96%)
[(4-Aminomethyl-cyclohexyl)-(4-chlorophenyl)-methyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=4-chlorophenyl) A15
LiAlH.sub.4 (1.89 g, 50 mmol) was added, under argon, to absolute
THF (300 ml); the mixture was heated to 60.degree. C., and the
oxime (7.5 g, 25 mmol), dissolved in THF (60 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (70 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered over kieselguhr. The filter
residue was washed with THF, the organic phases were combined, the
THF was removed in vacuo, and the residue was adjusted to pH 11
with 5N NaOH and extracted with ethyl acetate (4.times.40 ml). The
organic phase was dried over sodium sulfate and concentrated.
Yield: 6.3 g (90%), oil
.sup.13C-NMR (CDCl.sub.3): 25.22; 25.87; 26.58; 28.70; 30.36;
30.53; 30.59; 36.02; 38.76 (C.sub.4); 41.29; 41.39; 41.91
(N(CH.sub.3).sub.2); 45.64; 48.72; 70.72; 74.77 (CH); 127.46
(C.sub.arom); 127.52 (C.sub.arom); 130.27 (C.sub.arom); 132.11
(C.sub.arom); 132.15 (C.sub.arom); 134.80 (C.sub.arom); 135.72
(C.sub.arom).
4-(Dimethylamino-thiophen-2-yl-methyl)-cyclohexanecarbaldehyde
(R.sup.1=Me, R.sup.2=Me, R.sup.3=2-thienyl)
(Methoxymethyl)triphenylphosphonium chloride (20.56 g, 60 mmol) was
suspended in abs. THF (70 ml) under argon; potassium tert-butoxide
(6.73 g, 60 mmol), dissolved in abs. THF (70 ml), was added
dropwise at 0.degree. C., and stirring was then carried out for 15
min at 0.degree. C. The ketone (9.4 g, 40 mmol), dissolved in abs.
THF (70 ml), was then added dropwise at RT to the above solution,
and stirring was carried out overnight at RT. Hydrolysis was
carried out dropwise with water (60 ml) and 6N HCl (180 ml), while
cooling with ice-water. After one hour's stirring at RT, extraction
with diethyl ether (5.times.50 ml) was carried out, and the aqueous
phase was adjusted to pH 11 with 5N NaOH, extracted by shaking with
ethyl acetate (3.times.50 ml), dried over sodium sulfate and
concentrated in vacuo. The crude product was purified by flash
chromatography with ethyl acetate/cyclohexane (1:1).
Yield: 7.66 g (77%).
.sup.1H-NMR (DMSO, 600 MHz, selected signals): .delta.=2.03 (s,
3H); 2.05 (s, 3H); 3.44 (d, 1H, J=9.82 Hz); 3.52 (d, 1H, J=10.58
Hz); 9.54 (s, 1H); 9.58 (s, 1H).
.sup.13C-NMR (CDCl.sub.3): .delta.=23.74; 23.83; 25.80; 25.84;
26.98; 27.09; 29.15; 29.68; 39.13; 40.20; 40.98; 41.29
(N(CH.sub.3).sub.2); 47.48; 50.49; 67.81; 69.79; 123.61; 123.70;
125.89; 126.20; 126.24; 139.14; 139.48; 204.07; 204.82.
4-(Dimethylamino-thiophen-2-yl-methyl)-cyclohexanecarbaldehyde
oxime (R.sup.1=Me, R.sup.2=Me, R.sup.3=2-thiophene)
The carbaldehyde (7.54 g, 30 mmol) and hydroxylamine hydrochloride
(3.12 g, 45 mmol) were dissolved in abs. ethanol (100 ml); basic
ion exchanger Amberlyst A21 (21 g) was added thereto, and stirring
was carried out overnight at RT. The ion exchanger was filtered out
and washed with ethanol (2.times.50 ml). The solution was
concentrated, and the residue was adjusted to pH 11 with 5N NaOH.
The aqueous phase was extracted with ethyl acetate (3.times.50 ml),
and the organic phase was dried over sodium sulfate and
concentrated in vacuo.
Yield: 7.99 g (100%)
[(4-Aminomethyl-cyclohexyl)-thiophen-2-yl-methyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=2-thiophene) A16
LiAlH.sub.4 (2.27 g, 60 mmol) was added, under argon, to absolute
THF (300 ml); the mixture was heated to 60.degree. C., and the
oxime (7.99 g, 30 mmol), dissolved in THF (60 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (70 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered over kieselguhr. The filter
residue was washed with THF, the organic phases were combined, the
THF was removed in vacuo, and the residue was adjusted to pH 11
with 5N NaOH and extracted with ethyl acetate (3.times.50 ml). The
organic phase was dried over sodium sulfate and concentrated.
Yield: 6.72 g (89%), oil
.sup.13C-NMR (CDCl.sub.3): 25.93; 26.11; 26.24; 26.30; 29.97,
30.34; 30.42; 38.03; 40.65; 40.82; 41.18; 41.34
(N(CH.sub.3).sub.2); 46.19; 48.67; 65.58; 70.06; 123.61; 125.88;
126.23; 140.08.
4-(1-Dimethylamino-3-phenyl-propyl)-cyclohexane-carbaldehyde
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenethyl)
(Methoxymethyl)triphenylphosphonium chloride (20.56 g, 60 mmol) was
suspended in abs. THF (85 ml) under argon; potassium tert-butoxide
(6.73 g, 60 mmol), dissolved in abs. THF (70 ml), was added
dropwise at 0.degree. C., and stirring was then carried out for 15
min at 0.degree. C.
The ketone (10.2 g, 40 mmol), dissolved in abs. THF (60 ml), was
then added dropwise at RT to the above solution, and stirring was
carried out overnight at RT. Hydrolysis was carried out dropwise
with water (35 ml) and 6N HCl (90 ml), while cooling with
ice-water. After one hour's stirring at RT, extraction with diethyl
ether (10.times.50 ml) was carried out, and the aqueous phase was
adjusted to pH 11 with 5N NaOH, extracted with ethyl acetate
(3.times.50 ml), dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography with
ethyl acetate/cyclohexane (1:1).
Yield: 6.73 g (63%).
.sup.1H-NMR (DMSO, 600 MHz, selected signals): .delta.=2.18 (s,
3H); 2.20 (s, 3H); 9.54 (s, 1H); 9.61 (s, 1H).
.sup.13C-NMR (CDCl.sub.3): .delta.=24.35; 24.49; 26.00; 26.09;
26.85; 27.79; 29.07; 29.13; 35.27; 39.02; 40.98; 41.19; 46.99;
50.33; 66.85; 67.85; 70.54; 71.42; 125.40; 125.44; 128.02; 128.13;
131.15; 131.17; 142.45; 204.10; 205.01.
4-(1-Dimethylamino-3-phenyl-propyl)-cyclohexanecarbaldehyde oxime
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenethyl)
The aldehyde (6.55 g, 24 mmol) and hydroxylamine hydrochloride (2.5
g, 36 mmol) were dissolved in abs. ethanol (90 ml); basic ion
exchanger Amberlyst A21 (15.6 g) was added thereto, and stirring
was carried out overnight at RT. The ion exchanger was filtered off
and washed twice with ethanol (50 ml each time). The solution was
concentrated, and residue was adjusted to pH 11 with 5N NaOH. The
aqueous phase was extracted three times with ethyl acetate (50 ml
each time), and the organic phase was dried over sodium sulfate and
concentrated in vacuo.
Yield: 6.90 g (100%)
[1-(4-Aminomethyl-cyclohexyl)-3-phenyl-propyl]-dimethylamine
(R.sup.1=Me, R.sup.2=Me, R.sup.3=phenethyl) A17
LiAlH.sub.4 (1.82 g, 48 mmol) was added, under argon, to absolute
THF (360 ml); the mixture was heated to 60.degree. C., and the
oxime (6.90 g, 24 mmol), dissolved in THF (60 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (90 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered over kieselguhr. The filter
residue was washed with THF, the organic phases were combined, the
THF was removed in vacuo, and the residue was adjusted to pH 11
with 5N NaOH and extracted with ethyl acetate (4.times.40 ml). The
organic phase was dried over sodium sulfate and concentrated.
Yield: 5.6 g (85%), oil
.sup.13C-NMR (CDCl.sub.3): 25.93; 26.58; 27.09; 29.21; 29.90;
30.32; 30.73; 30.77; 35.38; 35.66; 38.73; (C.sub.4); 40.06; 40.90;
41.19 (N(CH.sub.3).sub.2); 48.78; 65.15; 68.22 (CH); 125.36;
127.99; 128.05; 142.69.
4-(Morpholino(phenyl)methyl)cyclohexanecarbaldehyde
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenyl)
A solution of potassium tert-butoxide (0.1 mol) in THF (100 ml) was
added dropwise at 0.degree. C., under argon, to a suspension of
(methoxytriphenyl)phosphonium chloride (0.1 mol) in absolute THF
(150 ml), and stirring was carried out for 15 min. The ketone (0.06
mol) in absolute THF (100 ml) was then added dropwise at 25.degree.
C., and stirring was carried out for 16 h. After addition of 6N HCl
at 0-5.degree. C. and stirring for one hour, extraction with ethyl
acetate (10.times.50 ml) was carried out. The aqueous phase was
then adjusted to pH 11 with 5N sodium hydroxide solution and
extracted with ethyl acetate (3.times.100 ml). The combined organic
phases were dried over Na.sub.2SO.sub.4 and filtered off. The
solvent was removed in vacuo, and the product was used in the next
stage without being purified further.
4-(Morpholino(phenyl)methyl)cyclohexanecarbaldehyde oxime
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenyl)
Amberlyst A21 (40 g) was added to a solution of the ketone (40
mmol) and hydroxylamine hydrochloride (4.17 g, 60 mmol) in absolute
ethanol (200 ml), and stirring was carried out for 20 h at
25.degree. C. After filtration and washing with ethanol
(2.times.200 ml), the solvent was removed in vacuo. The product was
used in the next stage without being purified further.
C-[4-(Morpholin-4-yl-phenyl-methyl)-cyclohexyl]-methylamine
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenyl) A18
The oxime (38.5 mmol) in THF (90 mol) was added dropwise at
60.degree. C. to a reaction mixture of lithium aluminium hydride
(77 mmol) in absolute THF (400 ml), and stirring was carried out
for 4 h at 60.degree. C. Water (100 ml) was then added slowly at
10.degree. C., and the reaction mixture was filtered off over
silica. The filter residue was washed with ethyl acetate, and the
solvent of the combined organic phases was removed in vacuo. The
product was purified by column chromatography (5-10%
methanol/dichloromethane).
4-(1-Morpholino-3-phenylpropyl)cyclohexancarbaldehyde
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenethyl)
A solution of potassium tert-butoxide (0.1 mol) in THF (100 ml) was
added dropwise at 0.degree. C., under argon, to a suspension of
(methoxytriphenyl)phosphonium chloride (0.1 mol) in absolute THF
(150 ml), and stirring was carried out for 15 min. The ketone (0.06
mol) in absolute THF (100 ml) was then added dropwise at 25.degree.
C., and stirring was carried out for 16 h. After addition of 6N HCl
at 0-5.degree. C. and stirring for one hour, extraction with ethyl
acetate (10.times.50 ml) was carried out. The aqueous phase was
then adjusted to pH 11 with 5N sodium hydroxide solution and
extracted with ethyl acetate (3.times.100 ml). The combined organic
phases were dried over Na.sub.2SO.sub.4 and filtered off. The
solvent was removed in vacuo, and the product was used in the next
stage without being purified further.
4-(1-Morpholino-3-phenylpropyl)cyclohexanecarbaldehyde oxime
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenethyl)
Amberlyst A21 (40 g) was added to a solution of the ketone (40
mmol) and hydroxylamine hydrochloride (4.17 g, 60 mmol) in absolute
ethanol (200 ml), and stirring was carried out for 20 h at
25.degree. C. After filtration and washing with ethanol
(2.times.200 ml), the solvent was removed in vacuo. The product was
used in the next stage without being purified further.
C-[4-(1-Morpholin-4-yl-3-phenyl-propyl)-cyclohexyl]-methylamine
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenethyl) A19
The oxime (38.5 mmol) in THF (90 ml) was added dropwise at
60.degree. C. to a reaction mixture of lithium aluminium hydride
(77 mmol) in absolute THF (400 ml), and stirring was carried out
for 4 h at 60.degree. C. Water (100 ml) was then added slowly at
10.degree. C., and the reaction mixture was filtered off over
silica. The filter residue was washed with ethyl acetate, and the
solvent of the combined organic phases was removed in vacuo. The
product was purified by column chromatography (5-10%
methanol/dichloromethane).
4-(Phenyl(pyrrolidin-1-yl)methyl)cyclohexanecarbaldehyde
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenethyl)
A solution of potassium tert-butoxide (0.1 mol) in THF (100 ml) was
added dropwise at 0.degree. C., under argon, to a suspension of
(methoxytriphenyl)phosphonium chloride (0.1 mol) in absolute THF
(150 ml), and stirring was carried out for 15 min. The ketone (0.06
mol) in absolute THF (100 ml) was then added dropwise at 25.degree.
C., and stirring was carried out for 16 h. After addition of 6N HCl
at 0-5.degree. C. and stirring for one hour, extraction with ethyl
acetate (10.times.50 ml) was carried out. The aqueous phase was
then adjusted to pH 11 with 5N sodium hydroxide solution and
extracted with ethyl acetate (3.times.100 ml). The combined organic
phases were dried over Na.sub.2SO.sub.4 and filtered off. The
solvent was removed in vacuo, and the product was used in the next
stage without being purified further.
4-(Phenyl(pyrrolidin-1-yl)methyl)cyclohexanecarbaldehyde oxime
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenethyl)
Amberlyst A21 (40 g) was added to a solution of the ketone (40
mmol) and hydroxylamine hydrochloride (4.17 g, 60 mmol) in absolute
ethanol (200 ml), and stirring was carried out for 20 h at
25.degree. C. After filtration and washing with ethanol
(2.times.200 ml), the solvent was removed in vacuo. The product was
used in the next stage without being purified further.
C-[4-(Phenyl-pyrrolidin-1-yl-methyl)-cyclohexyl]-methylamine
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenethyl) A20
The oxime (38.5 mmol) in THF (90 ml) was added dropwise at
60.degree. C. to a reaction mixture of lithium aluminium hydride
(77 mmol) in absolute THF (400 ml), and stirring was carried out
for 4 h at 60.degree. C. Water (100 ml) was then added slowly at
10.degree. C., and the reaction mixture was filtered off over
silica. The filter residue was washed with ethyl acetate, and the
solvent of the combined organic phases was removed in vacuo. The
product was purified by column chromatography (5-10%
methanol/dichloromethane).
4-(3-Phenyl-1-(pyrrolidin-1-yl)propyl)cyclohexanecarbaldehyde
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenyl)
A solution of potassium tert-butoxide (0.1 mol) in THF (100 ml) was
added dropwise at 0.degree. C., under argon, to a suspension of
(methoxytriphenyl)phosphonium chloride (0.1 mol) in absolute THF
(150 ml), and stirring was carried out for 15 min. The ketone (0.06
mol) in absolute THF (100 ml) was then added dropwise at 25.degree.
C., and stirring was carried out for 16 h. After addition of 6N HCl
at 0-5.degree. C. and stirring for one hour, extraction with ethyl
acetate (10.times.50 ml) was carried out. The aqueous phase was
then adjusted to pH 11 with 5N sodium hydroxide solution and
extracted with ethyl acetate (3.times.100 ml). The combined organic
phases were dried over Na.sub.2SO.sub.4 and filtered off. The
solvent was removed in vacuo, and the product was used in the next
stage without being purified further.
4-(3-Phenyl-1-(pyrrolidin-1-yl)propyl)cyclohexanecarbaldehyde oxime
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenyl)
Amberlyst A21 (40 g) was added to a solution of the ketone (40
mmol) and hydroxylamine hydrochloride (4.17 g, 60 mmol) in absolute
ethanol (200 ml), and stirring was carried out for 20 h at
25.degree. C. After filtration and washing with ethanol
(2.times.200 ml), the solvent was removed in vacuo. The product was
used in the next stage without being purified further.
C-[4-(3-Phenyl-1-pyrrolidin-1-yl-propyl)-cyclohexyl]-methylamine
(NR.sup.1R.sup.2=pyrrolidine, R.sup.3=phenyl) A21
The oxime (38.5 mmol) in THF (90 ml) was added dropwise at
60.degree. C. to a reaction mixture of lithium aluminium hydride
(77 mmol) in absolute THF (400 ml), and stirring was carried out
for 4 h at 60.degree. C. Water (100 ml) was then added slowly at
10.degree. C., and the reaction mixture was filtered off over
silica. The filter residue was washed with ethyl acetate, and the
solvent of the combined organic phases was removed in vacuo. The
product was purified by column chromatography (5-10%
methanol/dichloromethane).
Synthesis of the aminoethylcyclohexanes
The aminoethylcyclohexanes were prepared from the appropriately
substituted cyclohexylaldehydes by three-stage reactions by chain
extension (Wittig) and reaction with hydroxylamine hydrochloride
and subsequent cleavage with lithium aluminium hydride.
[4-(Dimethylamino-phenyl-methyl)-cyclohexyl]-acetaldehyde
(R.sup.3=phenyl)
(Methoxymethyl)triphenylphosphonium chloride (38.39 g, 0.112 mol)
was suspended in abs. THF (150 ml) under argon; potassium
tert-butoxide (12.56 g, 0.112 mol), dissolved in abs. THF (120 ml)
was added dropwise at 0.degree. C., and stirring was then carried
out for 15 min at 0.degree. C. (the solution turned a deep-orange
colour). The aldehyde (18.4 g, 0.075 mol), dissolved in abs. THF
(120 ml), was then added dropwise at RT, and stirring was carried
out overnight at RT. Hydrolysis was carried out dropwise with water
(50 ml) and 6N HCl (150 ml), while cooling with ice-water. After
one hour's stirring at RT, extraction with diethyl ether
(10.times.100 ml) was carried out. The aqueous phase was adjusted
to pH 11 with 5N NaOH, extracted by shaking with ethyl acetate
(3.times.80 ml), dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography with
ethyl acetate/cyclohexane (1:1).
Yield: 16.31 g (84%), oil
.sup.13C-NMR (CDCl.sub.3): 25.30; 25.92; 29.04; 29.19; 29.74;
30.86; 32.99; 33.02; 35.98; 38.31 (C.sub.4); 41.42; 42.06;
(N(CH.sub.3).sub.2); 48.04; 51.24; 71.82; 75.47 (CH); 126.64
(C.sub.arom); 126.68 (C.sub.arom); 127.39 (C.sub.arom); 127.46
(C.sub.arom); 129.15 (C.sub.arom); 136.20 (C.sub.arom); 137.11
(C.sub.arom); 202.27; 202.37 (CHO).
[4-(Dimethylamino-phenyl-methyl)-cyclohexyl]-acetaldehyde oxime
(R.sup.3=phenyl)
The carbaldehyde (11.04 g, 42.5 mmol) and hydroxylamine
hydrochloride (4.44 g, 64 mmol) were dissolved in abs. ethanol (150
ml); basic ion exchanger Amberlyst A21 (30 g) was added thereto,
and stirring was carried out for 4 h at RT. The ion exchanger was
filtered off and washed with ethanol (2.times.50 ml). The solution
was concentrated, the residue was adjusted to pH 11 with 5N NaOH,
the aqueous phase was extracted with ethyl acetate (3.times.50 ml),
and the organic phase was dried over sodium sulfate and
concentrated in vacuo.
Yield: 11.66 (100%)
.sup.13C-NMR (CDCl.sub.3): 25.41; 25.57; 28.87; 29.11; 30.92;
30.97; 32.33; 32.99; 33.67; 35.99; 36.10; 38.59 (C.sub.4); 41.31;
41.40; 42.11; 42.14 (N(CH.sub.3).sub.2); 71.74; 75.63 (CH); 126.71
(C.sub.arom); 127.46 (C.sub.arom); 129.26 (C.sub.arom); 137.26
(C.sub.arom); 150.95; 151.37; 151.56 (C.dbd.N--O).
2-[4-Dimethylamino-phenyl-methyl)-cyclohexyl]-ethylamine
(R.sup.3=phenyl) A22
LiAlH.sub.4 (3.22 g, 85 mmol) was added, under argon, to absolute
THF (400 ml); the mixture was heated to 60.degree. C., and the
oxime (11.66 g, 42.5 mmol), dissolved in THF (80 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (100 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered off over kieselguhr and the
kieselguhr was washed with THF. The combined THF solutions were
concentrated in vacuo, and the residue was adjusted to pH 11 with
5N NaOH and extracted with ethyl acetate (4.times.50 ml). The
organic phase was dried over sodium sulfate and concentrated by
evaporation.
Yield: 9.15 g (83%), oil
.sup.13C-NMR (CDCl.sub.3): 25.58; 26.08; 29.16; 29.21; 30.39;
31.10; 32.49; 33.16; 33.33; 35.54; 36.22; 38.80 (C.sub.4); 40.32;
41.36; 41.50; 42.11; (N(CH.sub.3).sub.2); 71.77; 75.66 (CH); 126.52
(C.sub.arom); 127.31 (C.sub.arom); 127.38 (C.sub.arom); 129.18
(C.sub.arom); 139.39 (C.sub.arom); 137.41 (C.sub.arom).
{4-[Dimethylamino-(4-fluorophenyl)-methyl]-cyclohexyl}-acetaldehyde
(R.sup.3=4-fluorophenyl)
(Methoxymethyl)triphenylphosphonium chloride (43.53 g, 127 mmol)
was suspended in abs. THF (200 ml) under argon; potassium
tert-butoxide (14.25 g, 127 mmol), dissolved in abs. THF (130 ml),
was added dropwise at 0.degree. C., and stirring was then carried
out for 15 min at 0.degree. C.
The aldehyde (22.3 g, 85 mmol), dissolved in abs. THF (130 ml), was
then added dropwise at RT, and stirring was carried out overnight
at RT. Hydrolysis was carried out dropwise with water (80 ml) and
6N HCl (200 ml), while cooling with ice-water. After one hour's
stirring at RT, extraction was carried out ten times with diethyl
ether (100 ml each time). The aqueous phase was adjusted to pH 11
with 5N NaOH, extracted by shaking three times with ethyl acetate
(100 ml each time), dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography with
ethyl acetate/cyclohexane (1:1). Yield: 15.8 g (67%)
.sup.13C-NMR (CDCl.sub.3): .delta.=25.08; 25.87; 28.80; 29.10;
29.13; 29.62; 30.82; 32.90; 33.08; 36.19; 38.43; 41.36; 42.01;
47.94; 51.17; 71.11; 74.69; 114.11; 114.20; 114.32; 130.32; 130.40;
132.00; 132.92; 160.31; 162.74; 202.15; 202.23.
{4-[Dimethylamino-(4-fluorophenyl)-methyl]-cyclohexyl}-acetaldehyde
oxime (R.sup.3=4-fluorophenyl)
The carbaldehyde (5.30 g, 20.0 mmol) and hydroxylamine
hydrochloride (2.08 g, 30 mmol) were dissolved in abs. ethanol (90
ml); basic ion exchanger Amberlyst A21 (14.8 g) was added thereto,
and stirring was carried out overnight at RT. The ion exchanger was
filtered off and washed with ethanol (2.times.50 ml). The solution
was concentrated, the residue was adjusted to pH 11 with 5N NaOH,
the aqueous phase was extracted with ethyl acetate (3.times.100
ml), and the organic phase was dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash
chromatography with EE/cyclohexane (2:1).
Yield: 3.50 (60%)
2-{(4-[Dimethylamino-(4-fluorophenyl)-methyl]-cyclohexyl}-ethylamine
A23 (R.sup.3=4-fluorophenyl)
LiAlH.sub.4 (2.35 g, 62 mmol) was added, under argon, to absolute
THF (450 ml); the mixture was heated to 60.degree. C., and the
oxime (9.10 g, 31.0 mmol), dissolved in THF (75 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (116 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered off over kieselguhr and the
kieselguhr was washed with THF. The combined THF solutions were
concentrated in vacuo, and the residue was adjusted to pH 11 with
5N NaOH and extracted with ethyl acetate (4.times.50 ml). The
organic phase was dried over sodium sulfate and concentrated in
vacuo.
Yield: 6.80 g (79%), oil
.sup.13C-NMR (CDCl.sub.3): 25.32; 26.03; 28.94; 29.08; 30.37;
31.06; 32.39; 32.90; 33.07; 33.26; 35.50; 37.81; 38.80 39.78
(C.sub.4); 41.33; 41.42; 42.09 (N(CH.sub.3).sub.2); 71.11; 74.89
(CH); 114.03; 114.11; 130.32; 130.40; 132.19; 133.18; 133.21;
160.27; 162.69.
{4-[Dimethylamino-(3-fluorophenyl)-methyl]-cyclohexyl}-acetaldehyde
(R.sup.3=3-fluorophenyl)
(Methoxymethyl)triphenylphosphonium chloride (26.73 g, 78 mmol) was
suspended in abs. THF (90 ml) under argon; potassium tert-butoxide
(8.75 g, 78 mmol), dissolved in abs. THF (90 ml), was added
dropwise at 0.degree. C., and stirring was then carried out for 15
min at 0.degree. C.
The aldehyde (13.69 g, 52 mmol), dissolved in abs. THF (90 ml), was
then added dropwise at RT, and stirring was carried out overnight
at RT. Hydrolysis was carried out dropwise with water (50 ml) and
6N HCl (150 ml), while cooling with ice-water. After one hour's
stirring at RT, extraction was carried out ten times with diethyl
ether (50 ml each time). The aqueous phase was adjusted to pH 11
with 5N NaOH, extracted by shaking three times with ethyl acetate
(100 ml each time), dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography with
ethyl acetate/cyclohexane (1:1).
Yield: 12.61 g (87%)
.sup.13C-NMR (CDCl.sub.3): .delta.=25.19; 25.83; 28.90; 29.06;
29.14; 29.68; 30.77; 32.92; 32.98; 33.10; 36.05; 38.36; 41.39;
42.04; 48.02; 51.20; 71.48; 75.07; 113.43; 113.49; 113.64; 113.69;
115.55; 115.76; 124.89; 128.70; 128.78; 128.88; 139.24; 140.08;
140.14; 161.09; 163.52; 202.19; 202.27.
{4-[Dimethylamino-(3-fluorophenyl)-methyl]-cyclohexyl}-acetaldehyde
oxime (R.sup.3=3-fluorophenyl)
The carbaldehyde (7.18 g, 25.8 mmol) and hydroxylamine
hydrochloride (2.71 g, 39 mmol) were dissolved in abs. ethanol (90
ml); basic ion exchanger Amberlyst A21 (20 g) was added thereto,
and stirring was carried out for 20 h at RT. The ion exchanger was
filtered out and washed with ethanol (2.times.50 ml). The solution
was concentrated, the residue was adjusted to pH 11 with 5N NaOH,
the aqueous phase was extracted with ethyl acetate (3.times.50 ml),
and the organic phase was dried over sodium sulfate and
concentrated in vacuo.
Yield: 7.54 (100%)
2-{4-[Dimethylamino-(3-fluorophenyl)-methyl]-cyclohexyl}-ethylamine
(R.sup.3=3-fluorophenyl) A24
LiAlH.sub.4 (1.97 g, 52 mmol) was added, under argon, to absolute
THF (300 ml); the mixture was heated to 60.degree. C., and the
oxime (7.54 g, 25.8 mmol), dissolved in THF (70 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (100 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered off over kieselguhr and the
kieselguhr was washed with THF. The combined THF solutions were
concentrated in vacuo, and the residue was adjusted to pH 11 with
5N NaOH and extracted with ethyl acetate (3.times.50 ml). The
organic phase was dried over sodium sulfate and concentrated in
vacuo.
Yield: 6.3 g (88%), oil
.sup.13C-NMR (CDCl.sub.3): 25.28; 25.84; 28.87; 28.98; 30.28;
32.30; 32.93; 33.13; 35.38; 36.16; 37.81; 38.69 (C.sub.4); 39.69;
41.20; 41.37; 41.94 (N(CH.sub.3).sub.2); 71.29; 75.11 (CH); 113.14;
113.18; 113.38; 115.41; 115.62; 124.73; 128.44; 128.53; 139.25;
140.27; 140.33; 160.91; 163.34.
{4-[(4-Chlorophenyl)-dimethylamino-methyl]-cyclohexyl}-acetaldehyde
(R.sup.3=4-chlorophenyl)
(Methoxymethyl)triphenylphosphonium chloride (25.02 g, 73 mmol) was
suspended in abs. THF (90 ml) under argon; potassium tert-butoxide
(8.19 g, 73 mmol), dissolved in abs. THF (90 ml), was added
dropwise at 0.degree. C., and stirring was then carried out for 15
min at 0.degree. C.
The aldehyde (13.86 g, 49 mmol), dissolved in abs. THF (90 ml), was
then added dropwise at RT, and stirring was carried out overnight
at RT. Hydrolysis was carried out dropwise with water (50 ml) and
6N HCl (150 ml), while cooling with ice-water. After one hour's
stirring at RT, extraction was carried out ten times with diethyl
ether (50 ml each time). The aqueous phase was adjusted to pH 11
with 5N NaOH, extracted by shaking three times with ethyl acetate
(100 ml each time), dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography with
ethyl acetate/cyclohexane (1:1). Yield: 12.07 g (84%).
.sup.13C-NMR (CDCl.sub.3): .delta.=25.06; 25.82; 28.74; 29.00;
29.13; 29.60; 30.77; 32.87; 32.94; 33.07; 36.06; 38.32; 41.38;
42.05; 47.95; 51.17; 71.23; 74.80; 127.58; 127.66; 130.31; 132.28;
132.34; 134.81; 135.77; 202.12; 202.20.
{4-[Dimethylamino-(4-chlorophenyl)-methyl]-cyclohexyl}-acetaldehyde
oxime (R.sup.3=4-chlorophenyl)
The carbaldehyde (6.72 g, 22.8 mmol) and hydroxylamine
hydrochloride (2.36 g, 34 mmol) were dissolved in abs. ethanol (90
ml); basic ion exchanger Amberlyst A21 (16 g) was added thereto,
and stirring was carried out for 20 h at RT. The ion exchanger was
filtered off and washed with ethanol (2.times.50 ml). The solution
was concentrated, the residue was adjusted to pH 11 with 5N NaOH,
the aqueous phase was extracted with ethyl acetate (3.times.50 ml),
and the organic phase was dried over sodium sulfate and
concentrated in vacuo.
Yield: 7.04 (100%)
2-{4-[Dimethylamino-(4-chlorophenyl)-methyl]-cyclohexyl}-ethylamine
(R.sup.3=4-chlorophenyl) A25
LiAlH.sub.4 (1.73 g, 45.6 mmol) was added, under argon, to absolute
THF (300 ml); the mixture was heated to 60.degree. C., and the
oxime (7.04 g, 22.8 mmol), dissolved in THF (60 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (100 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered off over kieselguhr and the
kieselguhr was washed with THF. The combined THF solutions were
concentrated in vacuo, and the residue was adjusted to pH 11 with
5N NaOH and extracted with ethyl acetate (3.times.50 ml). The
organic phase was dried over sodium sulfate and concentrated in
vacuo.
Yield: 5.76 g (86%), oil
.sup.13C-NMR (CDCl.sub.3): 25.67; 26.35; 29.23; 29.44; 30.74,
31.39; 33.41; 33.61; 35.86; 36.71; 38.20; 39.18; 40.17; 40.67;
41.72; 41.81; 42.50 (N(CH.sub.3).sub.2); 71.59; 75.37; 127.86;
127.95; 130.70; 132.52; 135.38; 136.45.
{4-[Dimethylamino-thiophen-2-yl-methyl]-cyclohexyl}-acetaldehyde
(R.sup.3=2-thienyl)
(Methoxymethyl)triphenylphosphonium chloride (28.79 g, 84 mmol) was
suspended in abs. THF (100 ml) under argon; potassium tert-butoxide
(9.42 g, 84 mmol), dissolved in abs. THF (100 ml), was added
dropwise at 0.degree. C., and stirring was then carried out for 15
min at 0.degree. C.
The aldehyde (14.08 g, 56 mmol), dissolved in abs. THF (100 ml),
was then added dropwise at RT, and stirring was carried out
overnight at RT. Hydrolysis was carried out dropwise with water (50
ml) and 6N HCl (150 ml), while cooling with ice-water. After one
hour's stirring at RT, extraction was carried out ten times with
diethyl ether (50 ml each time). The aqueous phase was adjusted to
pH 11 with 5N NaOH, extracted by shaking three times with ethyl
acetate (100 ml each time), dried over sodium sulfate and
concentrated in vacuo. The crude product was purified by flash
chromatography with ethyl acetate/cyclohexane (1:2). Yield: 11.48 g
(77%).
.sup.13C-NMR (CDCl.sub.3): .delta.=25.80; 25.88; 28.73; 29.95;
30.49, 32.23; 32.76; 37.89; 40.21; 40.88; 41.23; 48.36; 51.09;
66.02; 69.97; 123.19; 123.72; 125.95; 126.31; 139.42; 139.91;
202.61.
[4-(Dimethylamino-thiophen-2-yl-methyl)-cyclohexyl]-acetaldehyde
oxime (R.sup.3=2-thiophene)
The carbaldehyde (6.3 g, 23.7 mmol) and hydroxylamine hydrochloride
(2.5 g, 36 mmol) were dissolved in abs. ethanol (90 ml); basic ion
exchanger Amberlyst A21 (20 g) was added thereto, and stirring was
carried out for 20 h at RT. The ion exchanger was filtered off and
washed with ethanol (2.times.50 ml). The solution was concentrated,
the residue was adjusted to pH 11 with 5N NaOH, the aqueous phase
was extracted with ethyl acetate (3.times.50 ml), and the organic
phase was dried over sodium sulfate and concentrated in vacuo.
Yield: 6.64 (100%)
2-[4-(Dimethylamino-thiophen-2-yl-methyl)-cyclohexyl]-ethylamine
(R.sup.3=2-thiophene) A26
LiAlH.sub.4 (1.78 g, 47 mmol) was added, under argon, to absolute
THF (250 ml); the mixture was heated to 60.degree. C., and the
oxime (6.64 g, 23.7 mmol), dissolved in THF (60 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (100 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered off over kieselguhr and the
kieselguhr was washed with THF. The combined THF solutions were
concentrated in vacuo, and the residue was adjusted to pH 11 with
5N NaOH and extracted with ethyl acetate (3.times.50 ml). The
organic phase was dried over sodium sulfate and concentrated in
vacuo.
Yield: 5.62 g (89%), oil
.sup.13C-NMR (CDCl.sub.3): 25.97; 26.13; 28.72; 28.79; 30.15,
30.23; 30.74; 32.61; 32.90; 35.32; 38.22; 39.70; 40.09; 40.69;
40.84; 41.26 (N(CH.sub.3).sub.2); 70.14; 123.56; 123.60; 125.86;
126.21; 126.23; 139.70; 140.24.
[4-(1-Dimethylamino-3-phenyl-propyl)-cyclohexyl]-acetaldehyde
(R.sup.3=phenethyl)
(Methoxymethyl)triphenylphosphonium chloride (50.3 g, 147 mmol) was
suspended in abs. THF (150 ml) under argon; potassium tert-butoxide
(16.5 g, 147 mmol), dissolved in abs. THF (140 ml), was added
dropwise at 0.degree. C., and stirring was then carried out for 15
min at 0.degree. C.
The aldehyde (27.0 g, 98 mmol), dissolved in abs. THF (150 ml), was
then added dropwise at RT, and stirring was carried out overnight
at RT. Hydrolysis was carried out dropwise with water (102 ml) and
6N HCl (240 ml), while cooling with ice-water. After one hour's
stirring at RT, extraction was carried out five times with diethyl
ether (200 ml each time). The aqueous phase was adjusted to pH 11
with 5N NaOH, extracted by shaking three times with ethyl acetate
(200 ml each time), dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography with
ethyl acetate/cyclohexane (1:1). Yield: 18.1 g (64%)
.sup.13C-NMR (CDCl.sub.3): .delta.=25.55; 26.19; 29.04; 29.15;
29.35; 29.85; 31.00; 32.87; 32.68; 33.04; 35.33; 38.49; 40.86;
41.13; 47.51; 51.15; 65.48; 68.09.
[4-(1-Dimethylamino-3-phenyl-propyl)-cyclohexyl]-acetaldehyde oxime
(R.sup.3=phenethyl)
The carbaldehyde (12.6 g, 44.0 mmol) and hydroxylamine
hydrochloride (4.60 g, 66.0 mmol) were dissolved in abs. ethanol
(200 ml); basic ion exchanger Amberlyst A21 (32 g) was added
thereto, and stirring was carried out overnight at RT. The ion
exchanger was filtered off and washed with ethanol (2.times.50 ml).
The solution was concentrated, the residue was adjusted to pH 11
with 5N NaOH, the aqueous phase was extracted with ethyl acetate
(3.times.50 ml), and the organic phase was dried over sodium
sulfate and concentrated in vacuo.
Yield: 13.3 (100%)
{1-[4-(2-Amino-ethyl)-cyclohexyl]-3-phenyl-propyl}-dimethylamine
(R.sup.3=phenethyl) A27
LiAlH.sub.4 (4.25 g, 112 mmol) was added, under argon, to absolute
THF (600 ml); the mixture was heated to 60.degree. C., and the
oxime 71 (17.1 g, 56.0 mmol), dissolved in THF (150 ml), was added
dropwise. After 4 hours' stirring at 60.degree. C., water (360 ml)
was added dropwise, while cooling with an ice bath (10.degree. C.),
and the reaction solution was filtered off over kieselguhr and the
kieselguhr was washed with THF. The combined THF solutions were
concentrated in vacuo, and the residue was adjusted to pH 11 with
5N NaOH and extracted with ethyl acetate (5.times.100 ml). The
organic phase was dried over sodium sulfate and concentrated in
vacuo.
Yield: 16.2 g (100%), oil
.sup.13C-NMR (CDCl.sub.3): 25.67; 26.44; 29.07; 29.16; 30.05,
30.22; 31.32; 31.80; 33.30; 35.24; 35.37; 37.26; 39.77; 40.30;
40.85; 41.15; 41.40 (N(CH.sub.3).sub.2); 65.61; 68.29; 125.53;
127.68; 128.16; 128.200; 142.91.
Synthesis of the Piperidine Derivatives
Commercially available isonipecotic acid methyl ester was used as
starting material for the piperidine derivatives; it was first
N-protected, in order subsequently to reduce the ester function to
the aldehyde. The introduction of the N,N-dimethyl(aryl)methanamine
radical was carried out analogously to the cyclohexylamine
derivatives. Deprotection yielded the desired product.
Methyl 1-(4-methoxybenzyl)piperidine-4-carboxylate
4-Methoxybenzyl chloride (1.10 g, 6.98 mmol) was added dropwise to
a solution of isonipecotic acid methyl ester (1.00 g, 6.98 mmol)
and triethylamine (1.40 g, 14 mmol) in THF (30 ml), and stirring
was carried out for 72 h at 60.degree. C. 5% sodium hydrogen
carbonate solution (50 ml) was then added to the reaction mixture,
and extraction with ethyl acetate (3.times.50 ml) was carried out.
The combined organic phases were dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash
chromatography with cyclohexane/ethyl acetate (2:1).
Yield: 1.23 g (67%) of methyl
1-(4-methoxybenzyl)piperidine-4-carboxylate
.sup.1H-NMR (DMSO-d.sub.6): 1.53 (dq, 2H); 1.77 (dd, 2H); 1.93 (dt,
2H); 2.28 (tt, 1H); 2.71 (td, 2H); 3.35 (s, 2H); 3.58 (s, 3H); 3.72
(s, 3H); 6.86 (d, 2H); 7.17 (d, 2H).
1-(4-Methoxybenzyl)piperidine-4-carbaldehyde
A 1.5 M solution of diisobutylaluminium hydride in toluene (3.12
ml, 4.68 mmol) was added dropwise under argon at -78.degree. C., in
the course of 30 minutes, to a solution of methyl
1-(4-methoxybenzyl)piperidine-4-carboxylate (1.23 g, 4.68 mmol) in
toluene (30 ml), and stirring was then carried out for 30 min at
that temperature. Methanol (15 ml) was then added dropwise in such
a manner that the internal temperature remained at -78.degree. C.,
before the mixture was then slowly warmed to room temperature.
Saturated sodium chloride solution (20 ml) was added to the
reaction mixture, and the suspension was filtered through sea sand.
The organic phase was dried over sodium sulfate and concentrated in
vacuo. The residue was purified by flash chromatography with
cyclohexane/ethyl acetate (1:3).
Yield: 750 mg (69%) of
1-(4-methoxybenzyl)piperidine-4-carbaldehyde
.sup.1H-NMR (DMSO-d.sub.6): 1.47 (dtd, 2H); 1.78 (m, 2H); 2.00 (dt,
2H); 2.27 (m, 1H); 2.66 (td, 2H); 3.36 (s, 2H); 3.73 (s, 3H); 6.86
(d, 2H); 7.18 (d, 2H); 9.57 (s, 1H).
2-(Dimethylamino)-2-(1-(4-methoxybenzyl)piperidin-4-yl)acetonitrile
(R.sup.1, R.sup.2=methyl)
40% aqueous dimethylamine solution (2.66 ml, 21 mmol),
1-(4-methoxybenzyl)-piperidine-4-carbaldehyde (750 mg, 3.2 mmol)
and potassium cyanide (688 mg, 10.6 mmol) were added, while cooling
with ice, to a mixture of 4 N hydrochloric acid (1.2 ml) and
methanol (5 ml). The reaction mixture was stirred for 5 d at room
temperature, then water (50 ml) was added and extraction with ethyl
acetate was carried out (3.times.50 ml). The combined organic
phases were dried over sodium sulfate and concentrated in
vacuo.
Yield: 875 mg (95%) of
2-(dimethylamino)-2-(1-(4-methoxybenzyl)piperidine-4-yl)acetonitrile
.sup.1H-NMR (DMSO-d.sub.6): 1.22-1.29 (m, 2H); 1.57 (ddt, 1H);
1.76-1.97 (m, 4H); 2.18 (s, 6H); 2.73-2.88 (m, 3H); 3.36 (s, 3H);
3.73 (s, 2H); 6.85 (d, 2H); 7.16 (d, 2H).
(1-(4-Methoxybenzyl)piperidin-4-yl)-N,N-dimethyl(phenyl)methanamine
(R.sup.1, R.sup.2=methyl, R.sup.3=phenyl)
A 2 M phenylmagnesium chloride solution in THF (3.75 ml, 7.5 mmol)
was added dropwise to an ice-cooled solution of
2-(dimethylamino)-2-(1-(4-methoxybenzyl)piperidin-4-yl)acetonitrile
(875 mg, 3.0 mmol) in THF (20 ml), and then the reaction mixture
was heated slowly to room temperature and stirred for 16 h.
Saturated ammonium chloride solution (50 ml) was then added to the
reaction solution, extraction with ethyl acetate (3.times.50 ml)
was carried out, the combined organic phases were dried over sodium
sulfate and concentrated in vacuo, and the residue was purified by
flash chromatography with chloroform/methanol/triethylamine
(9:1:0.1).
Yield: 832 mg (82%) of
1-(1-(4-methoxybenzyl)piperidin-4-yl)-N,N-dimethyl-1-phenylmethanamine
.sup.1H-NMR (DMSO-d.sub.6): 0.84-1.18 (m, 3H); 1.74-1.89 (m, 4H);
1.99 (s, 6H); 2.68 (d, 1H); 2.80 (d, 1H); 3.07 (d, 1H, J=8.9 Hz);
3.32 (s, 2H); 3.71 (s, 3H); 6.84 (d, 2H); 7.15 (q, 4H); 7.21-7.33
(m, 3H).
Benzyl 4-((dimethylamino)(phenyl)methyl)piperidine-1-carboxylate
(R.sup.1, R.sup.2=methyl, R.sup.3=phenyl)
Chloroformic acid benzyl ester (1.50 g, 1.25 ml, 8.86 mmol) was
added to a solution of
1-(1-(4-methoxybenzyl)piperidin-4-yl)-N,N-dimethyl-1-phenylmethanamine
(3.00 g, 8.86 mmol) in DCM (50 ml), and stirring was carried out
for 30 min at room temperature. Sodium hydrogen carbonate solution
(40 ml) was then added to the reaction mixture, the phases were
separated, and the aqueous phase was extracted with DCM (2.times.30
ml). The combined organic phases were dried over sodium sulfate and
concentrated in vacuo, and the residue was purified by flash
chromatography with chloroform/methanol/triethylamine
(100:5:1).
Yield: 2.32 g (74%) of benzyl
4-((dimethylamino)(phenyl)methyl)piperidine-1-carboxylate
.sup.1H-NMR (DMSO-d.sub.6): 0.82 (ddd, 2H); 0.97 (ddd, 2H); 1.27
(d, 1H); 2.00 (s, 6H); 2.69-2.84 (m, 2H); 3.11 (d, 1H); 3.89 (d,
1H); 4.03 (d, 1H); 5.03 (s, 2H); 7.14 (m, 2H); 7.20-7.35 (m,
8H).
N,N-Dimethyl-1-phenyl-1-(piperidin-4-yl)methanamine (R.sup.1,
R.sup.2=methyl, R.sup.3=phenyl) A28
33% hydrogen bromide in glacial acetic acid (20 ml) was added to a
solution of benzyl
4-((dimethylamino)(phenyl)methyl)piperidine-1-carboxylate (2.32 g,
6.58 mmol) in glacial acetic acid (20 ml), and stirring was carried
out for 1.5 h at room temperature. A solid was precipitated by
addition of diethyl ether. The supernatant solution was decanted
off; diethyl ether was added repeatedly to the residue, and the
supernatant solution was decanted off again each time. The residue
was dried in vacuo and dissolved in methanol (20 ml); strongly
basic ion exchanger Dowex 1.times.2-200 was added thereto, and
stirring was carried out for 1 h at room temperature. The mixture
was then filtered, the filter residue was washed with methanol, and
the filtrate was concentrated in vacuo.
Yield: 1.09 g (76%) of
N,N-dimethyl-1-phenyl-1-(piperidin-4-yl)methanamine
.sup.1H-NMR (DMSO-d.sub.6): 1.06 (ddd, 1H); 1.23 (td, 2H); 1.72 (br
s, 1H); 1.99 (s, 6H); 2.20 (dd, 1H); 2.66 (dt, 1H); 2.77 (dt, 1H);
3.03 (d, 1H); 3.10 (d, 1H); 3.17 (d, 1H); 7.15 (d, 2H); 7.25 (m,
1H); 7.34 (m, 2H).
##STR00027##
tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate
Triethylamine (1.5 equivalents) and Boc anhydride (1.2 equivalents)
were added at 0.degree. C. to a solution of
4-hydroxymethylpiperidine in DMC, and stirring was carried out for
1 h at 25.degree. C. After addition of DCM, the organic phase was
separated off and washed with water and saturated aqueous NaCl
solution. After drying the organic phase over Na.sub.2SO.sub.4 and
filtration, the solvent was removed in vacuo. The product was
purified by column chromatography (30% ethyl acetate/hexane).
tert-Butyl 4-formylpiperidine-1-carboxylate
DMSO (2.2 equivalents) was added at -78.degree. C., under an inert
gas atmosphere, to a solution of oxalyl chloride (1.1 equivalents)
in dry CH.sub.2Cl.sub.2, and stirring was carried out for 1 h. A
solution of N-Boc-4-piperidinemethanol (1 equivalent) in dry DCM
was added dropwise to the reaction mixture at -70.degree. C., and
stirring was carried out for 2 h. After addition of triethylamine
(2.5 equivalents), the reaction solution was allowed to warm to RT,
and saturated aqueous NH.sub.4Cl solution and DCM were added
thereto. The organic phase was separated and washed with water and
saturated aqueous NaCl solution. After drying the organic phase
over Na.sub.2SO.sub.4 and filtration, the solvent was removed in
vacuo. The product was used in the next stage without being
purified further.
tert-Butyl
4-((1H-benzo[d][1,2,3]triazol-1-yl)(morpholino)methyl)piperidin-
e-1-carboxylate
The aldehyde (23.4 mmol), morpholine (23.4 mmol) and
1H-benzotriazole (23.4 mmol) were heated for 16 h under reflux in
benzene (60 ml), and the resulting water of reaction was removed by
means of a water separator. The benzene was removed in vacuo and
the residue was used directly in the next stage.
tert-Butyl 4-(morpholino(phenyl)methyl)piperidine-1-carboxylate
(NR.sup.1R.sup.2=morpholine, R.sup.3=phenyl) X1
A solution of the benzotriazole adduct (23.5 mmol) in THF was added
dropwise to a solution of the Grignard reagent (47.1 mmol) in THF,
and stirring was carried out for 16 h at 25.degree. C. The reaction
solution was cooled to 0.degree. C.; saturated aqueous NH.sub.4Cl
solution was added thereto, and then extraction with ethyl acetate
(2.times.300 ml) was carried out. The organic phase was washed with
water and saturated aqueous NaCl solution. After drying the organic
phase over Na.sub.2SO.sub.4 and filtration, the solvent was removed
in vacuo. The product was purified by column chromatography (2-5%
methanol/dichloromethane).
tert-Butyl 4-(morpholino(benzyl)methyl)piperidine-1-carboxylate
carboxylate (NR.sup.1R.sup.2=morpholine, R.sup.3=benzyl) X2
A solution of the benzotriazole adduct (23.5 mmol) in THF was added
dropwise to a solution of the Grignard reagent (47.1 mmol) in THF,
and stirring was carried out for 16 h at 25.degree. C. The reaction
solution was cooled to 0.degree. C.; saturated aqueous NH.sub.4Cl
solution was added thereto, and then extraction with ethyl acetate
(2.times.300 ml) was carried out. The organic phase was washed with
water and saturated aqueous NaCl solution. After drying the organic
phase over Na.sub.2SO.sub.4 and filtration, the solvent was removed
in vacuo. The product was purified by column chromatography (2-5%
methanol/dichloromethane).
The amines A29 and A30 were obtained from X1 and X2 by acid
cleavage of the Boc group.
Synthesis of amine structural units A31-A35
##STR00028##
Stage 1. Diisobutylaluminium hydride (15.3 mmol, 1.5 M solution in
toluene) was added dropwise at -70.degree. C., under an argon
atmosphere, to a solution of piperidine-1,4-dicarboxylic acid
1-tert-butyl ester 4-ethyl ester (15 mmol) in dry toluene (20 ml),
and stirring was carried out for 2 hours at that temperature. When
the reaction was complete (TLC monitoring), methanol (20 ml) was
added at -70.degree. C. and the reaction mixture was heated to RT.
A saturated sodium chloride solution was added (30 ml), and the
mixture was filtered over silica gel. Washing with ethyl acetate
was then carried out, and the aqueous phase was separated off and
extracted again with ethyl acetate. The combined organic phases
were washed with saturated sodium chloride solution and then dried
over sodium sulfate and concentrated. The crude product was used
further without being purified further.
Stage 2. tert-Butyl 4-formylpiperidine-1-carboxylate (15 mmol),
N-methylpiperazine (15 mmol) and benzotriazole (15 mmol) in benzene
(60 ml) were heated under reflux in a Dean-Stark water separator.
The solvent was then removed under reduced pressure. The resulting
crude product was used further without being purified further.
Stage 3. tert-Butyl
4-((1H-benzo[d][1,2,3]triazol-1-yl)(4-methylpiperazin-1-yl)-methyl)piperi-
dine-1-carboxylate (12 mmol) in THF was added dropwise at 0.degree.
C. to a solution of the corresponding Grignard reagent in THF (60
mmol). The reaction mixture was heated to 25.degree. C. and stirred
at that temperature for 16 h (TLC monitoring). The mixture was then
cooled to 0.degree. C., saturated ammonium chloride solution was
added, and extraction with ethyl acetate was carried out. The
organic phase was washed in succession with water and saturated
sodium chloride solution and dried over sodium sulfate. The solvent
was removed and the resulting crude product was purified by column
chromatography (silica gel, DCM/methanol, 98:2.fwdarw.95:5).
Stage 4. TFA (20% in DCM, 5 ml/mmol) was added at 0.degree. C. to
the Boc-protected compound, and stirring was then carried out for 3
h at room temperature (TLC monitoring). The solvent was removed
completely and the crude product (TFA salt) was used further
without being purified further.
The following amine structural units were prepared according to the
process described above:
TABLE-US-00002 Name R.sup.3 A31 1-((3-fluorophenyl)(piperidin-4-yl)
methyl)-4-methyl-piperazine ##STR00029## A32
1-((4-fluorophenyl)(piperidin-4-yl) methyl)-4-methyl-piperazine
##STR00030## A33 1-methyl-4-(phenyl(piperidin-4-yl)
methyl)-piperazine ##STR00031## A34
1-methyl-4-(2-phenyl-1-(piperidin-4-yl) ethyl)-piperazine
##STR00032## A35 1-methyl-4-(3-phenyl-1-(piperidin-4-yl)
propyl)-piperazine ##STR00033##
b) Preparation of the Acid Structural Units
TABLE-US-00003 TABLE 2 Examples of acid structural units S1
2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-
yl)-acetic acid S2
2-(2-(3,4-dichloro-N-methylphenylsulfonamido)phenyl)acetic acid S3
3-((3,4-dichloro-N-methylphenylsulfonamido)methyl)benzoic acid S4
2-(3,4-dichloro-N-methylphenylsulfonamido)benzoic acid S5
2-(3,4-dichloro-N-methylphenylsulfonamido)-4,5,6,7-
tetrahydrobenzo-[b]thiophene-3-carboxylic acid S6
1-(3,4-dichlorophenylsulfonyl)indoline-2-carboxylic acid S7
1-(4-methoxyphenylsulfonyl)indoline-2-carboxylic acid S8
2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)acetic acid
S9 1-(4-methoxy-N-methylphenylsulfonamido)cyclohexanecarboxylic
acid S10 5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoic
acid S11
2-(1-(2,4-dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetic acid
S12 2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-
tetrahydroquinoxalin-2-yL)acetic acid S13
2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)acetic acid S14
2-(1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)acetic acid S15
2-(2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)
acetic acid S16 3-(naphthalene-2-sulfonamido)-3-phenylpropionic
acid S17
3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propionic
acid
Synthesis of
2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-ace-
tic acid S1
N-Bromosuccinimide (30.6 g, 172 mmol) was added in portions, over a
period of 15 min, to a stirred solution of
1,2,3,4-tetrahydroisoquinoline (20.80 g, 156 mmol) in DCM (400 ml).
The reaction solution was stirred until the starting material had
reacted completely (TLC monitoring). NaOH (100 ml of a 30% aqueous
solution) was then added, and stirring was carried out for 1 h at
room temperature. The phases were separated and the organic phase
was washed with water (200 ml). The product was extracted with HCl
(10% aqueous solution, 2.times.200 ml), and the combined acidic
aqueous solutions were washed with DCM. The mixture was then
rendered basic (pH 9) with ammonia, and the oil that had separated
off was extracted with DCM (3.times.200 ml). Drying over sodium
sulfate and concentration yielded a yellowish oil.
Yield: (20.0 g, 98%)
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid
3,4-Dihydroisoquinoline (20.0 g, 152 mmol) and malonic acid (15.9
g, 152 mmol) were mixed thoroughly at room temperature. The mixture
was immersed in an oil bath preheated to 120.degree. C., and was
mixed further manually. After 30 min, no further evolution of gas
was to be observed and the mixture was cooled to room temperature.
The solid residue (29.0 g) was recrystallised directly from aqueous
2-propanol.
Yield: 16.2 g, 56%
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid methyl ester
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid (7.90 g, 41.3
mmol) was dissolved in methanol (200 ml), and H.sub.2SO.sub.4 (4.4
ml, 82.6 mmol) was added under a nitrogen atmosphere. The reaction
solution was heated under reflux and, when the reaction was
complete, was stirred overnight at room temperature. The methanol
was removed in vacuo and the resulting residue was taken up in
ethyl acetate (200 ml). The solution was washed with saturated
NaHCO.sub.3 solution (150 ml), dried (sodium sulfate) and
concentrated.
Yield: 7.50 g (88%)
Methyl
2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-y-
l)-acetate
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid methyl ester
(7.49 g, 36.5 mmol) was dissolved in DCM (200 ml), and
triethylamine (11.7 ml, 83 mmol) was added thereto. The reaction
solution was cooled to 0.degree. C., and a solution of
3,4-dichlorobenzenesulfonyl chloride (8.14 g, 33.2 mmol) in DCM
(100 ml) was added dropwise. After 3 h, 0.5 M HCl (100 ml) was
added. After phase separation, the organic phase was washed with
water, dried (sodium sulfate) and concentrated. Purification was
carried out by column chromatography on silica gel (heptane/ethyl
acetate 4:1).
Yield: 14.84 g
2-(2-(3,4-Dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-acet-
ic acid S1
To a mixture of methyl
2-(2-(3,4-dichlorophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-ace-
tate (14.84 g, 33.2 mmol), THF (200 ml) and water (120 ml) was a
and stirred at room temperature. After 4 h, aqueous NaOH solution
(6 M, 60 ml) was again added, and stirring was carried out
overnight at room temperature. The reaction solution was
concentrated under reduced pressure. 6 M HCl solution (125 ml) and
DCM (400 ml) were added. After phase separation, the organic phase
was washed with saturated NaCl solution, dried (sodium sulfate) and
concentrated. For purification, the product was recrystallised from
2-propanol.
Yield: 11.30 g
2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)phenyl)-acetic acid
S2
Thionyl chloride (5.2 ml, 71.4 mmol) was added dropwise, with
stirring and while cooling with ice, to a solution of
2-aminophenylacetic acid (7.2 g, 47.6 mmol) in methanol (150 ml).
The reaction mixture was stirred overnight at room temperature. The
reaction solution was concentrated, and thionyl chloride residues
were removed by dragging out with toluene and DCM. 10.3 g
(contaminated with starting material) of the were obtained in the
form of a brown solid. The crude product was used further without
being purified further.
2-(2-(3,4-Dichlorophenylsulfonamido)phenyl)acetic acid methyl
ester
2-Aminophenylacetic acid methyl ester (10.2 g, 39.45 mmol) was
dissolved in DCM (200 ml). There were then added first pyridine
(12.4 ml, 151.71 mmol) and 3,4-dichlorobenzenesulfonyl chloride
(11.8 ml, 75.87 mmol) in DCM (50 ml). The reaction solution was
stirred overnight and then diluted with DCM and washed in
succession with 0.5 M KHSO.sub.4 solution, saturated NaHCO.sub.3
solution and saturated NaCl solution, dried over sodium sulfate and
concentrated. Purification was carried out by column chromatography
on silica gel (DCM).
Yield: 14.3 g (96%)
2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)phenyl)-acetic acid
methyl ester
2-(2-(3,4-Dichlorophenylsulfonamido)phenyl)acetic acid methyl ester
(14.3 g, 38.21 mmol) and methyl iodide (8.2 ml, 132.25 mmol) were
dissolved in acetone (300 ml); K.sub.2CO.sub.3 (7.3 g, 52.90 mmol)
was added thereto, and stirring was carried out overnight at
40.degree. C. in a closed flask. The suspension was cooled and then
filtered, concentrated, filtered over silica gel (eluant DCM) and
concentrated.
Yield: 15.3 g
2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)phenyl)-acetic acid
S2
2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)phenyl)acetic acid
methyl ester (13.7 g, 34.26 mmol) was dissolved in a mixture of
methanol/dioxane/4 M NaOH (15/4/1) (266 ml, 52.92 mmol NaOH), and
then further 4 M NaOH (39.7 ml, 158.76 mmol) was added. The
resulting clear solution was stirred overnight at room temperature
and then concentrated in vacuo. The residue was taken up in ethyl
acetate and washed with 0.5 M KHSO.sub.4. The aqueous phase was
then extracted several times with ethyl acetate. The combined
organic phases were washed with saturated NaCl solution, dried over
sodium sulfate and concentrated.
Yield: 13.0 g
Synthesis of
3-((3,4-dichloro-N-methylphenylsulfonamido)methyl)benzoic acid
S3
3,4-Dichloro-N-methylbenzenesulfonamide
Methylamine hydrochloride (5.5 g, 81.46 mmol) was dissolved in DCM
(300 ml), and Et.sub.3N (40 ml, 285.11 mmol) was added thereto. The
reaction solution was then cooled to 0.degree. C.;
3,4-dichlorobenzenesulfonyl chloride (20.00 g, 81.46 mmol)
dissolved in DCM (50 ml) was then added dropwise, and stirring was
carried out overnight at room temperature (TLC monitoring, silica
gel, ethyl acetate). When the reaction was complete, 0.5 N HCl was
added, the phases were separated, and the organic phase was washed
with water and dried (sodium sulfate). The solvent was removed
using a rotary evaporator. Purification was carried out by column
chromatography on silica gel (gradient heptane/ethyl acetate 4:1 to
2:1).
Yield: 13.0 g (66%)
Methyl
3-((3,4-dichloro-N-methylphenylsulfonamido)methyl)-benzoate
3,4-Dichloro-N-methylbenzenesulfonamide (12.9 g, 53.72 mmol) was
dissolved in acetone (200 ml), and K.sub.2CO.sub.3 (14.8 g, 107.44
mmol) was added thereto. Methyl (3-bromomethyl)benzoate (24.6 g,
107.44 mmol) was then added, and the suspension was heated
overnight at 40.degree. C. After cooling to room temperature, the
solid material was filtered off and the filtrate was concentrated
using a rotary evaporator. Purification was carried out by column
chromatography on silica gel (heptane/ethyl acetate 4:1).
Yield: 19.9 g (95%)
3-((3,4-Dichloro-N-methylphenylsulfonamido)methyl)-benzoic acid
S3
Methyl 3-((3,4-dichloro-N-methylphenylsulfonamido)methyl)benzoate
(19.9 g, 51.25 mmol) was dissolved in a mixture of
methanol/dioxane/4 M NaOH (15/4/1, 384 ml, 76.88 mmol NaOH, 1.5
eq.), and further 4 M NaOH (57.7 ml, 230.63 mmol, 4.5 eq.) was
added thereto. After stirring overnight at room temperature,
concentration was carried out using a rotary evaporator. Ethyl
acetate (300 ml) was added to the residue, and washing with 0.5 M
KHSO.sub.4 was carried out. The aqueous phase was extracted again
with ethyl acetate (200 ml). The combined organic phases were dried
(sodium sulfate) and concentrated in vacuo.
Ethyl acetate was again added, and the suspension was filtered and
concentrated.
Yield: 11.6 g (60%)
Synthesis of 2-(3,4-dichloro-N-methylphenylsulfonamido)benzoic acid
S4
Methyl 2-(3,4-dichlorophenylsulfonamido)benzoate
Methyl 2-aminobenzoate (10 g, 66.2 mmol) was dissolved in DCM (100
ml), and pyridine (8.1 ml, 99.2 mmol, 1.5 eq.) was added thereto. A
solution of 3,4-dichlorobenzenesulfonyl chloride (24.4 g, 99.2
mmol, 1.5 eq.) in DCM (150 ml) was then added dropwise at 0.degree.
C., and the reaction mixture was stirred overnight at room
temperature. TLC monitoring (silica gel, DCM) showed complete
conversion. When the reaction was complete, the reaction solution
was diluted with DCM (250 ml) and washed with 0.5 M KHSO.sub.4 (500
ml), saturated NaHCO.sub.3 (500 ml) and saturated NaCl solution
(500 ml). The organic phase was dried over sodium sulfate and
concentrated in vacuo. For purification, filtration over a thin
layer of silica gel was carried out (gradient: heptane/DCM (3:1) to
DCM).
Yield: 21.9 g (91%)
Methyl 2-(3,4-dichloro-N-methylphenylsulfonamido)benzoate
Methyl 2-(3,4-dichlorophenylsulfonamido)benzoate (21.3 g, 59.1
mmol) was dissolved in acetone (300 ml), and K.sub.2CO.sub.3 (16.3
g, 118.3 mmol, 2 eq.) was added thereto. Methyl iodide (7.4 ml,
118.3 mmol, 2 eq.) was then added, and the suspension was heated
overnight at 40.degree. C. The solid materials were filtered off
and the filtrate was concentrated using a rotary evaporator.
Purification was carried out by filtration over silica gel
(DCM).
Yield: 21.8 g (98%) The product was used further directly.
2-(3,4-Dichloro-N-methylphenylsulfonamido)benzoic acid S4
Methyl 2-(3,4-dichloro-N-methylphenylsulfonamido)benzoate (21.0 g,
56.1 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH
(15/4/1, 420 ml, 84 mmol NaOH, 1.5 eq.), and further 4 M NaOH (63
ml, 252 mmol, 4.5 eq.) was added. The solution was stirred
overnight at room temperature and then concentrated using a rotary
evaporator. Ethyl acetate (800 ml) was added to the residue, and
the mixture was washed with 0.5 M KHSO.sub.4 (1000 ml). The aqueous
phase was then extracted three times with ethyl acetate (350 ml
each time), and the combined organic phases were washed with
saturated NaCl solution (500 ml). The organic phase was dried
(sodium sulfate) and concentrated in vacuo.
The residue was washed with diisopropyl ether and dried overnight
at 40.degree. C. in a drying cabinet.
Yield: 18.83 g (90%)
Synthesis of
2-(3,4-dichloro-N-methylphenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxylic acid S5
tert-Butyl
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
Morpholine (6.7 ml, 76 mmol) was added to a mixture of
cyclohexanone (5.00 g, 50.9 mmol), tert-butyl cyanoacetate (7.91 g,
56.0 mmol) and sulfur (1.80 g, 56.0 mmol) in ethanol (abs., 150
ml). The reaction solution was stirred overnight at 50.degree. C.
and then cooled to room temperature. After filtration, the filtrate
was concentrated and the residue was taken up in ethyl acetate (100
ml), washed with water (2.times.50 ml), saturated NaCl solution
(2.times.50 ml), dried (sodium sulfate) and concentrated.
Purification was carried out by column chromatography on silica gel
(heptane/ethyl acetate=10/1).
Yield: 12.73 g (99%)
tert-Butyl
2-(3,4-dichlorophenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]-th-
iophene-3-carboxylate
tert-Butyl
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (12.26 g,
48.4 mmol) was dissolved in DCM (150 ml), and pyridine (6.0 ml, 74
mmol) was added thereto. A solution of 3,4-dichlorobenzenesulfonyl
chloride (8.4 ml, 54 mmol) was then added, and the mixture was
heated for 17 h under reflux and then cooled to room temperature.
Water was added (100 ml), and stirring was carried out overnight at
room temperature. The phases were then separated (pH organic
phase.apprxeq.2), washed with saturated NaHCO.sub.3 solution, dried
(sodium sulfate) and concentrated in vacuo.
Yield: (21.64 g, 97%)
tert-Butyl
2-(3,4-dichloro-N-methylphenylsulfonamido)-4,5,6,7-tetrahydrobe-
nzo-[b]thiophene-3-carboxylate
tert-Butyl
2-(3,4-dichlorophenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-c-
arboxylate (21.64 g, 46.8 mmol) was dissolved in acetone (200 ml),
and K.sub.2CO.sub.3 (12.9 g, 93.6 mmol) was added thereto. Methyl
iodide (5.83 ml, 93.6 mmol) was then added, and the suspension was
heated overnight at 40.degree. C. After cooling to room
temperature, water and saturated NaCl solution were added and the
product was extracted with ethyl acetate. The organic phase was
dried (sodium sulfate) and the product was purified by
crystallization from methanol.
Yield: (16.47 g, 74%)
The mother liquor was concentrated and further product was obtained
by crystallization from methanol.
Yield: 1.57 g, 7%
Overall yield: 18.04 g (81%)
2-(3,4-Dichloro-N-methylphenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]-thio-
phene-3-carboxylic acid S5
TFA (30 ml, 404 mmol) was added to a solution of tert-butyl
2-(3,4-dichloro-N-methylphenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxylate (8.00 g, 16.8 mmol) in DCM (100 ml), and
stirring was carried out for 1 h at room temperature. The reaction
mixture was concentrated, and the TFA that remained was removed
with toluene, DCM and diethyl ether. The residue was washed twice
with diisopropyl ether.
Yield: 6.49 g, 92%
Synthesis of 1-(3,4-dichlorophenylsulfonyl)indoline-2-carboxylic
acid S6
Indoline-2-carboxylic acid methyl ester
Thionyl chloride (12.1 ml, 167.2 mmol) was added dropwise, with
stirring and while cooling with ice, to a solution of
indoline-2-carboxylic acid (24.8 g, 152.0 mmol) in methanol (500
ml). The reaction mixture was stirred overnight at 40.degree. C.
The reaction solution was concentrated and thionyl chloride
residues were removed by dragging out with diethyl ether (3
times).
Yield: 33.5 g
Methyl 1-(3,4-dichlorophenylsulfonyl)indoline-2-carboxylate
Indoline-2-carboxylic acid methyl ester (33.0 g, 149.7 mmol) was
dissolved in DCM (400 ml), and pyridine (37.8 ml, 463.2 mmol) was
added thereto. A solution of 3,4-dichlorobenzenesulfonyl chloride
(24.1 ml, 154.4 mmol) dissolved in DCM (100 ml) was then added, and
the mixture was stirred overnight under reflux and then cooled to
room temperature. The mixture was diluted with DCM and washed in
succession with 0.5 M KHSO.sub.4, saturated NaHCO.sub.3 solution
and saturated NaCl solution. The organic phase was dried (sodium
sulfate) and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(heptane/ethyl acetate=2:1).
Yield: 50.4 g (87%)
1-(3,4-Dichlorophenylsulfonyl)indoline-2-carboxylic acid S6
Methyl 1-(3,4-dichlorophenylsulfonyl)indoline-2-carboxylate (49.8
g, 128.92 mmol) was dissolved in a mixture of methanol/dioxane/4 M
NaOH (15/4/1, 960 ml, 193.38 mmol NaOH, 1.5 eq.), and further 4 M
NaOH (145 ml, 580.14 mmol, 4.5 eq.) was added thereto. The solution
was stirred overnight at room temperature and then concentrated
using a rotary evaporator. Ethyl acetate was added to the residue,
and the mixture was washed with 0.5 M KHSO.sub.4. The aqueous phase
was then extracted three times with ethyl acetate, and the combined
organic phases were washed with saturated NaCl solution (500 ml),
dried (sodium sulfate) and concentrated in vacuo. The residue was
washed with diethyl ether, filtered and dried.
Yield: 22.3 g (46%)
Synthesis of 1-(4-methoxyphenylsulfonyl)indoline-2-carboxylic acid
S7
Methyl 1-(4-methoxyphenylsulfonyl)indoline-2-carboxylate
Indoline-2-carboxylic acid methyl ester (32.7 g, 151.8 mmol) was
dissolved in DCM (400 ml), and pyridine (37.4 ml, 459.0 mmol) was
added thereto. A solution of 4-methoxybenzenesulfonyl chloride
(31.6 g, 153 mmol) dissolved in DCM (100 ml) was then added, and
stirring was carried out overnight at room temperature. The mixture
was diluted with DCM and washed in succession with 0.5 M
KHSO.sub.4, saturated NaHCO.sub.3 solution and saturated NaCl
solution. The organic phase was dried (sodium sulfate) and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (heptane/ethyl acetate 2:1).
Yield: 47.1 g (89%)
1-(4-Methoxyphenylsulfonyl)indoline-2-carboxylic acid S7
Methyl 1-(4-methoxyphenylsulfonyl)indoline-2-carboxylate (47.1 g,
135.6 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH
(15/4/1,1020 ml, 203.4 mmol NaOH, 1.5 eq.), and further 4 M NaOH
(153 ml, 610.2 mmol, 4.5 eq.) was added thereto. The solution was
stirred overnight at room temperature and then concentrated using a
rotary evaporator. Ethyl acetate was added to the residue, and the
mixture was washed with 0.5 M KHSO.sub.4. The aqueous phase was
extracted again with ethyl acetate, and the combined organic phases
were washed with saturated NaCl solution, dried (sodium sulfate)
and concentrated in vacuo. The residue was washed with diethyl
ether, filtered and dried.
Yield: 38.1 g (84%)
Synthesis of
2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)acetic acid
S8
2-(Piperidin-2-yl)acetic acid
A solution of chromium trioxide (20 g, 200 mmol) in water (300 ml)
and concentrated sulfuric acid (40 g, 73.6 ml) was added dropwise
in the course of 1.5 h, while cooling with ice, to a solution of
2-piperidineethanol (10.0 g, 10.1 ml, 77.4 mmol) in water (10 ml).
The reaction mixture was stirred for 3 h at room temperature. The
solution was then rendered alkaline with saturated aqueous barium
hydroxide solution. Carbon dioxide was then passed into the
solution, and the resulting suspension was filtered through Celite.
The filtrate was concentrated in vacuo.
Yield: 9.26 g (83%)
.sup.1H-NMR (D.sub.2O): 1.50-1.70 (m, 3H); 1.80-1.93 (m, 2H);
1.93-2.02 (m, 1H); 2.76 (d, 2H); 3.04 (dt, 1H); 3.38-3.45 (m, 1H);
3.45-3.57 (m, 1H).
2-(1-(3-(Trifluoromethyl)phenylsulfonyl)piperidin-2-yl)acetic acid
S8
A solution of 3-trifluoromethylbenzenesulfonic acid chloride (2.70
g, 11 mmol) in 1,4-dioxane (10 ml) was added slowly, in the course
of 1 h, to a solution of 2-(piperidin-2-yl)acetic acid (1.43 g, 10
mmol) in 1,4-dioxane (5 ml) and 1 N sodium hydroxide solution (22
ml). The mixture was then stirred for 4.5 h at room temperature,
then acidified with 1 N hydrochloric acid and subsequently
extracted with DCM (3.times.60 ml). The combined organic phases
were dried over sodium sulfate and concentrated in vacuo.
Yield: 917 mg (26%)
.sup.1H-NMR (DMSO-d.sub.6): 1.05-1.55 (m, 6H); 2.25 (dd, 1H); 2.66
(dd, 1H); 2.99 (dt, 1H); 3.69 (br dd, 1H); 4.41 (1H, m); 7.87 (1H,
t); 8.03-8.08 (m, 2H) 8.13 (d, 1H), 12.33 (br s, 1H).
Synthesis of 1-(4-methoxy-N-methylphenylsulfonamido)carboxylic acid
S9
1-Amino-cyclohexanecarboxylic acid methyl ester hydrochloride
1-Amino-cyclohexanecarboxylic acid (49 g, 342 mmol) was added to a
solution, cooled to 0.degree. C., of thionyl chloride (49.6 ml, 684
mmol) in methanol (750 ml). The reaction mixture was stirred for 4
h under reflux and then overnight at room temperature. Then the
mixture was heated again for 3 h under reflux and stirred overnight
again at room temperature. The reaction solution was concentrated
and the thionyl chloride residues were removed by dragging out with
methanol and diethyl ether.
Yield: 66.64 g
Methyl 1-(4-methoxyphenylsulfonamido)-cyclohexanecarboxylate
1-Amino-cyclohexanecarboxylic acid methyl ester hydrochloride (32
g, 165 mmol) was suspended in DCM (1000 ml), and
diisopropylethylamine (84.9 ml, 496 mmol) was added thereto. A
solution of 4-methoxybenzenesulfonyl chloride (51.2 g, 248 mmol)
dissolved in DCM (150 ml) was added dropwise at 0.degree. C., and
stirring was carried out overnight at room temperature. Aqueous 1 M
HCl (150 ml) and water (50 ml) were added and the phases were
separated. The organic phase was dried over sodium sulfate and
concentrated to dryness. The product was purified by column
chromatography on silica gel (DCM/methanol 99:1).
The mixed fractions were again purified by column chromatography on
silica gel (gradient: DCM/heptane 5:1 to DCM/methanol 99:1).
Overall yield: 37.8 g (70%)
Methyl
1-(4-methoxy-N-methylphenylsulfonamido)cyclohexanecarboxylate
Methyl 1-(4-methoxyphenylsulfonamido)cyclohexanecarboxylate (27 g,
82.5 mmol) was dissolved in acetone (450 ml), and K.sub.2CO.sub.3
(22.8 g, 165 mmol) was added thereto. Methyl iodide (10.3 ml, 165
mmol) was then added, and the suspension was heated overnight at
40.degree. C. in a closed flask. Because the reaction was not yet
complete (TLC monitoring, heptane/ethyl acetate 2:1), methyl iodide
(7.7 ml, 124 mmol) was again added and stirring was carried out
over the weekend at room temperature. Methyl iodide (2.6 ml, 41.8
mmol) was again added, and stirring was carried out overnight at
40.degree. C. After cooling, the solid materials were filtered off
and the filtrate was concentrated to dryness. The crude product was
used further without being purified further.
1-(4-Methoxy-N-methylphenylsulfonamido)carboxylic acid S9
Methyl
1-(4-methoxy-N-methylphenylsulfonamido)cyclohexanecarboxylate (28.2
g, 82.5 mmol) was dissolved in a mixture of methanol/dioxane/4 M
NaOH (15/4/1, 620 ml, 124 mmol NaOH, 1.5 eq.), and further 4 M NaOH
(93 ml, 372 mmol, 4.5 eq.) was added thereto. Because no reaction
could be detected after stirring overnight at room temperature, the
mixture was first heated for 8 h at 68.degree. C., refluxed over
the weekend at room temperature and again overnight. The mixture
was then concentrated using a rotary evaporator. Ethyl acetate (500
ml) was added to the residue, and washing with 0.5 M KHSO.sub.4
(500 ml) was carried out. The aqueous phase was extracted again
with ethyl acetate (200 ml), dried (sodium sulfate) and
concentrated in vacuo. The aqueous phase was acidified with HCl (2
M, 300 ml) and extracted three times with DCM (300 ml each
time).
Overall yield: 26.5 g
Synthesis of 5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoic
acid S10
5-(2,4,6-Trichloro-phenylsulfonamido)pentanoic acid
A solution of 2,4,6-trichlorobenzenesulfonic acid chloride (3.00 g,
11 mmol) in 1,4-dioxane (50 ml) was added dropwise to a solution of
5-aminovaleric acid hydrochloride (1.50 g, 10 mmol) in 1 N sodium
hydroxide solution (30 ml). The reaction mixture was stirred for 18
h at room temperature, and 1,4-dioxane was then distilled off in
vacuo. The aqueous phase was extracted with ethyl acetate
(3.times.50 ml) and then adjusted to pH 1 with concentrated
hydrochloric acid. The acidic aqueous phase was extracted with
ethyl acetate (3.times.60 ml). The combined organic phases were
dried over sodium sulfate and concentrated in vacuo.
Yield: 2.28 g (64%)
.sup.1H-NMR (DMSO-d.sub.6): 1.33-1.57 (m, 4H); 2.12 (t, 2H); 2.87
(q, 2H); 4.00 (very br s, 1H); 7.85 (s, 1H); 8.22 (t, 1H).
Methyl 5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoate
Cesium carbonate (449 mg, 1.38 mmol) and then methyl iodide (487
mg, 213 .mu.l, 3.45 mmol) were added to a solution of
5-(2,4,6-trichlorophenylsulfon-amido)pentanoic acid (250 mg, 0.69
mmol) in a 1:1 mixture of N,N-dimethylformamide/acetone (10 ml),
and stirring was carried out for 4 h at 50.degree. C. The reaction
mixture was then concentrated in vacuo; toluene was added
repeatedly (3.times.) to the residue, concentration in vacuo was
carried out again each time, and then the mixture was taken up in
5% sodium hydrogen carbonate solution and extracted with ethyl
acetate (3.times.30 ml). The combined organic phases were dried
over sodium sulfate and concentrated in vacuo.
Yield: 188 mg (69%)
.sup.1H-NMR (DMSO-d.sub.6): 1.40-1.60 (m, 4H); 2.30 (t, 2H); 2.82
(s, 3H); 3.32 (t, 2H); 3.57 (s, 3H); 7.89 (s, 2H).
5-(2,4,6-Trichloro-N-methylphenylsulfonamido)pentanoic acid S10
A solution of lithium hydroxide (18.2 mg, 0.76 mmol) in water (3
ml) was added to a solution of methyl
5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoate (178 mg,
0.45 mmol) in THF (5 ml), and stirring was carried out for 18 h at
room temperature. THF was then concentrated in vacuo, water was
added to the residue, and extraction with DCM (2.times.20 ml) was
carried out. The aqueous phase was adjusted to pH 1-2 with
concentrated hydrochloric acid and extracted with ethyl acetate
(3.times.20 ml). The combined organic extracts were dried over
sodium sulfate and concentrated in vacuo.
Yield: 111 mg (64%)
.sup.1H-NMR (DMSO-d.sub.6): 1.40-1.58 (m, 4H); 2.21 (t, 2H); 2.83
(s, 3H); 3.24 (t, 2H); 7.89 (s, 2H); 12.0 (s, 1H).
Synthesis of
2-(1-(2,4-dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetic acid
S11
Ethyl 2-(3-oxopiperazin-2-yl)acetate
Ethylenediamine (1.17 ml, 17.42 mmol) and diethyl maleate (3 g,
17.42 mmol) were stirred for 16 h at 55.degree. C. in propanol (30
ml). The solvent was removed in vacuo and the residue was dried in
vacuo. The product was used in the next stage without being
purified further.
Yield: 3.4 g (100%)
Ethyl
2-(1-(2,4-dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetate
To a solution, cooled to 0.degree. C., of the piperazine derivative
(2.5 g, 13.4 mmol) in DCM (55 ml) and triethylamine (4.2 ml, 33.5
mmol) there was added dropwise at that temperature a
2,4-dichlorobenzenesulfonyl chloride (3 g, 13.4 mmol) in DCM (25
ml), and then a catalytic amount of DMAP was added thereto. The
reaction solution was stirred for 16 h at room temperature and then
diluted with DCM. The reaction mixture was washed first with 0.5 M
HCl and then with water and saturated NaCl solution. The organic
phase was dried over sodium sulfate and concentrated to dryness.
The product was purified by column chromatography.
Yield: 2.85 g (58%)
2-(1-(2,4-Dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetic acid
S11
Lithium hydroxide (0.92 mg, 21.9 mmol) was added to a cooled
solution of ethyl
2-(1-(2,4-dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetate (2.7
g, 7.3 mmol) in methanol (25 ml) and water (6 ml), and stirring was
carried out for 16 h at room temperature (TLC monitoring). The
solvent was removed using a rotary evaporator and the residue was
taken up in water. The aqueous phase was washed with diethyl ether
and acidified with HCl, and the product was extracted with ethyl
acetate. The organic phase was then washed with saturated NaCl
solution. The organic phase was dried over sodium sulfate and
concentrated to dryness.
Yield: 2.5 g (97%)
2-(1-(3,4-Dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-
acetic acid S12
Methyl 2-(3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)acetate
Orthophenylenediamine (10 g, 92.4 mmol) and diethyl maleate (45 g,
646.8 mmol) were refluxed for 75 h in propanol. The solvent was
removed using a rotary evaporator and the residue was purified by
column chromatography (ethyl acetate/hexane 1:1).
Yield: 4 g (18.5%)
Methyl
2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxali-
n-2-yl)acetate
A solution of 3,4-dichlorobenzenesulfonyl chloride (4 ml, 25.6
mmol) in DCM (60 ml) was added dropwise to a solution (3 g, 12.8
mmol) in DCM (125 ml) and pyridine (5.17 ml, 64 mmol), and then a
catalytic amount of DMAP was added thereto. The reaction solution
was stirred for 16 h at room temperature and then diluted with DCM.
The reaction mixture was washed with copper sulfate solution, 1 M
HCl and sodium carbonate solution, water and saturated NaCl
solution. The organic phase was dried over sodium sulfate and
concentrated to dryness. The product was purified by column
chromatography (ethyl acetate/hexane 4:6); yield: 3.12 g (55%).
2-(1-(3,4-Dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-
acetic acid S12
Lithium hydroxide (0.041 g, 10.95 mmol) was added to a cooled
solution of methyl
2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxal-
in-2-yl)acetate (2.7 g, 7.3 mmol) in THF (45 ml) and water (45 ml),
and stirring was carried out for 48 h at room temperature (TLC
monitoring). The solvent was removed using a rotary evaporator and
the residue was taken up in water. The aqueous phase was extracted
with ethyl acetate and then washed with saturated NaCl solution.
The organic phase was dried over sodium sulfate and concentrated to
dryness.
Yield: 0.6 g (23%)
2-(1-(3,4-Dichlorophenylsulfonyl)pyrrolidin-2-yl)acetic acid
S13Pyrrolidin-2-ylacetic acid methyl ester
Thionyl chloride (1.8 ml, 25.2 mmol) was added dropwise to a
solution, cooled to 0.degree. C., of pyrrolidin-2-ylacetic acid
hydrochloride (1.4 g, 8.4 mmol) in methanol (35 ml), and the
mixture was heated for 16 h at gentle boiling and then cooled to
room temperature. The solvent was removed azeotropically in vacuo
with benzene. Yield: 1.5 g (100%)
Methyl 2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)acetate
A solution of 3,4-dichlorobenzenesulfonyl chloride (1.88 g, 7.65
mmol) in DCM (15 ml) was added dropwise at 0.degree. C. to a
solution, cooled to 0.degree. C., of pyrrolidin-2-ylacetic acid
methyl ester (1.5 g, 8.4 mmol) in DCM (33 ml) and triethylamine was
(2.66 ml, 21 mmol), and stirring was then carried out for 90
minutes at room temperature. 0.5 M HCl (20 ml) was then added, and
stirring was carried out for a further 15 minutes. The organic
phase was separated, washed with water and dried over sodium
sulfate. The solvent was removed using a rotary evaporator and the
product was used in the next stage without being purified further.
Yield: 2.1 g (77%)
2-(1-(3,4-Dichlorophenylsulfonyl)pyrrolidin-2-yl)acetic acid
S13
Lithium hydroxide (0.75 mg, 18 mmol) was added to a cooled solution
of methyl 2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)acetate
(2.1 g, 6 mmol) in methanol (20 ml) and water (20 ml), and stirring
was carried out for 16 h at room temperature (TLC monitoring). The
solvent was removed using a rotary evaporator and the residue was
taken up in water. The aqueous phase was washed with ethyl acetate
and acidified with 1 M HCl, and then the product was extracted with
ethyl acetate and the organic phase was washed with saturated NaCl
solution. The organic phase was dried over sodium sulfate and
concentrated to dryness. Yield: 2.0 g (99%)
2-(1-(3,4-Dichlorophenylsulfonyl)piperidin-2-yl)acetic acid S14
Piperidin-2-ylacetic acid methyl ester hydrochloride
Thionyl chloride (1.8 ml, 25.2 mmol) was added dropwise to a
solution, cooled to 0.degree. C., of piperidin-2-ylacetic acid
hydrochloride (1.5 g, 8.4 mmol) in methanol (35 ml), and the
mixture was heated for 16 h at gentle boiling and then cooled to
room temperature. The solvent was removed azeotropically in vacuo
with benzene. Yield: 1.3 g (100%)
Methyl 2-(1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)acetate
A solution of 3,4-dichlorobenzenesulfonyl chloride (1.88 g, 7.65
mmol) in DCM (15 ml) was added at 0.degree. C. to a solution,
cooled to 0.degree. C., of piperidin-2-ylacetic acid methyl ester
hydrochloride (1.3 g, 8.4 mmol) in DCM (33 ml) and triethylamine
(2.66 ml, 21 mmol), and stirring was then carried out for 90
minutes at room temperature. 0.5 M HCl (20 ml) was then added, and
stirring was carried out for a further 15 minutes. The organic
phase was separated off, washed with water and dried over sodium
sulfate. The solvent was removed using a rotary evaporator and the
product was used in the next stage without being purified further.
Yield: 1.9 g (63%)
2-(1-(3,4-Dichlorophenylsulfonyl)piperidin-2-yl)acetic acid S14
Lithium hydroxide (0.75 mg, 18 mmol) was added to a cooled solution
of methyl 2-(1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)acetate
(2.1 g, 6 mmol) in methanol (20 ml) and water (20 ml), and stirring
was carried out for 16 h at room temperature (TLC monitoring). The
solvent was removed using a rotary evaporator and the residue was
taken up in water. The aqueous phase was washed with ethyl acetate
and then acidified with 1 M HCl, and the product was extracted with
ethyl acetate, and the organic phase was then washed with saturated
NaCl solution. The organic phase was dried over sodium sulfate and
concentrated to dryness. Yield: 2.9 g (98%)
2-(2-(4-Methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic
acid S15
Methyl
2-(2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)--
acetate
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid methyl ester
(9.55 g, 46.5 mmol) was dissolved in DCM (150 ml), and
triethylamine (14.9 ml, 106 mmol) was added thereto. The reaction
mixture was cooled to 0.degree. C., and a solution of
methoxybenzenesulfonyl chloride (8.74 g, 42.3 mmol) in DCM (100 ml)
was added dropwise thereto. The reaction mixture was stirred
overnight at room temperature. For working up, 100 ml of a 0.5 M
HCl solution were added and then the phases were separated. The
organic phase was first washed with water and then dried over
sodium sulfate. The crude product was purified by column
chromatography on silica gel (mobile phase: DCM).
Yield: 15.22 g (96%)
2-(2-(4-Methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic
acid S15
A 6 M aqueous NaOH solution was added to a mixture of methyl
2-(2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate
(15.22 g, 40.54 mmol) in THF (200 ml) and water (120 ml), and
stirring was carried out overnight at room temperature. The solvent
was then removed under reduced pressure, and a 6 M aqueous HCl
solution (125 ml) and DCM (400 ml) were added. The phases were
separated and then the organic phase was washed with concentrated
NaCl solution, dried over sodium sulfate and concentrated. Yield:
14.65 g (100%)
3-(Naphthalene-2-sulfonamido)-3-phenylpropionic acid S16
##STR00034##
Stage 1. Thionyl chloride (19.1 g, 162 mmol) was added dropwise to
a solution, cooled to 0.degree. C., of 3-amino-3-phenylpropionic
acid (8.9 g, 54 mmol) in methanol (150 ml). The reaction mixture
was then heated for 12 h under reflux (TLC monitoring). The solvent
was removed completely and the residue was dried in vacuo. The
crude product was used in the next stage without being purified
further.
Stage 2. The amino alcohol (1.1 eq.) was dissolved in DCM (4
ml/mmol), and triethylamine (2.2 eq.) was added thereto. The
solution was cooled to 0.degree. C., a solution of the
corresponding sulfonic acid chloride (1 eq.) dissolved in DCM (2.3
ml/mmol) was added dropwise, and stirring was carried out for 1.5 h
at RT. When the reaction was complete, HCl (0.5 M, 2.3 ml/mmol) was
added and the phases were separated, washed with water, dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
by column chromatography (silica gel, ethyl acetate/hexane,
3:7).
Stage 3. LiOH.H.sub.2O (2 eq.) was added at a reaction temperature
of 0.degree. C. to a solution of the ester (1 eq.) in a
methanol/water mixture (3:1, 10 ml/mmol). The reaction mixture was
stirred for 16 h at RT. The solvent was removed under reduced
pressure and the residue was taken up in water and washed with DCM.
The aqueous phase was then carefully acidified with HCl (1 N) and
extracted with ethyl acetate. The organic phase was washed with
water and sat. NaCl solution and dried over Na.sub.2SO.sub.4. After
removal of the solvent, the product was obtained in adequate
purity.
3-(1-(4-Chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propionic
acid S17
##STR00035##
Stage 1. H.sub.2SO.sub.4 (12.8 ml, 240 mmol) was added to a
solution of 3-(2-pyridyl)-acrylic acid (23.88 g, 160 mmol) in
methanol (750 ml). The reaction mixture was heated overnight under
reflux and, after cooling to RT, was poured into saturated aqueous
NaHCO.sub.3 solution (1000 ml). The methanol was removed using a
rotary evaporator, and the aqueous phase was extracted twice with
ethyl acetate (400 ml). The organic phase was washed with saturated
NaCl solution (500 ml), dried over Na.sub.2SO.sub.4 and
concentrated. The crude product of methyl 3-(pyridin-2-yl)acrylate
was used in the next stage without being purified further.
Stage 2. Methyl 3-(pyridin-2-yl)acrylate (22.15 g, 136 mmol) was
dissolved in THF (300 ml) and chloroform (10.9 ml), and PtO.sub.2
(3.08 g, 13.6 mmol, 0.1 eq.) was added under a nitrogen atmosphere.
The solution was first rinsed for 10 min. with nitrogen and then
stirred overnight under a H.sub.2 atmosphere (8 bar). After
cooling, rinsing with nitrogen was first carried out again, the
catalyst was removed by filtration over filtering earth and then
rinsed with DCM, and the filtrate was concentrated to dryness in
vacuo. The methyl 3-(piperidin-2-yl)propionate hydrochloride was
used in the next stage without being purified further.
Stage 3. The amino alcohol (1.1 eq.) was dissolved in DCM (4
ml/mmol), and triethylamine (2.2 eq.) was added thereto. The
solution was cooled to 0.degree. C., a solution of the
corresponding sulfonic acid chloride (1 eq.) dissolved in DCM (2.3
ml/mmol) was added dropwise, and stirring was carried out for 1.5 h
at RT. When the reaction was complete, HCl (0.5 M, 2.3 ml/mmol) was
added and the phases were separated, washed with water, dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
by column chromatography on silica gel (silica gel, hexane/ethyl
acetate, 6:1.fwdarw.3:1).
Stage 4. Aqueous NaOH solution (6 M, 3 ml/mmol) was added to a
solution of the ester (1 eq.) in THF (3 ml/mmol). After a reaction
time of 1 h, the solvent was removed using a rotary evaporator and
cooling to 0.degree. C. was carried out. HCl (6 M, 3 ml/mmol) was
added and extraction with ethyl acetate was carried out. The
organic phase was dried over Na.sub.2SO.sub.4 and concentrated.
Synthesis of the carbamates
Synthesis of phenyl
3-(4-methoxy-N,2,3,6-tetramethylphenylsulfonamido)-propylcarbamate
V1
N--(2-Cyanoethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide
4-Methoxy-2,3,6-trimethylbenzenesulfonyl chloride (5.00 g, 20 mmol)
was added at room temperature to a solution of
3-methylaminopropionitrile (1.50 g, 18.3 mmol) and triethylamine
(5.50 g, 55 mmol) in THF (30 ml), and stirring was carried out for
16 h. Ethyl acetate (50 ml) was then added to the reaction mixture,
and washing with sodium hydrogen carbonate solution (3.times.50 ml)
was carried out. The organic phase was dried over sodium sulfate
and concentrated in vacuo.
Yield: 4.92 g (91%)
.sup.1H-NMR (DMSO-d.sub.6): 2.09 (s, 3H); 2.44 (s, 3H); 2.59 (s,
3H); 2.68 (s, 3H); 2.76 (t, 2H); 3.30 (t, 2H); 3.84 (s, 3H); 6.87
(s, 1H).
N-(3-Aminopropyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide
Platinum(IV) oxide (400 mg) was added to a solution of
N--(2-cyanoethyl)-4-methoxy-2,3,6--N-tetramethylbenzenesulfonamide
(4.92 g, 16.6 mmol) and concentrated sulfuric acid (3.20 g, 33.2
mmol) in ethanol (100 ml), and stirring was carried out for 3 h at
room temperature under a hydrogen atmosphere of 3 bar. Sodium
hydrogen carbonate was then added to the solution, and the mixture
was filtered and concentrated in vacuo. The residue was taken up in
sodium hydrogen carbonate solution (50 ml) and extracted with DCM
(3.times.50 ml). The combined organic phases were dried over sodium
sulfate and concentrated in vacuo.
Yield: 4.65 g (93%)
.sup.1H-NMR (DMSO-d.sub.6): 1.53 (td, 2H); 2.09 (s, 3H); 2.43 (s,
3H); 2.50 (m, 2H); 2.58 (s, 3H); 2.61 (s, 3H); 3.06 (t, 2H); 3.21
(br s, 2H); 3.84 (s, 3H); 6.84 (s, 1H).
Phenyl
3-(4-methoxy-N,2,3,6-tetramethylphenylsulfonamido)-propylcarbamate
V1
Chloroformic acid phenyl ester (2.29 g, 14.6 mmol) was added at
room temperature to a solution of
N--(3-aminopropyl)-4-methoxy-2,3,6--N-tetramethyl
-benzenesulfonamide (3.99 g, 13.3 mmol) and triethylamine (4.0 g,
5.5 ml, 40 mmol) in THF (60 ml), and stirring was carried out for
16 h at that temperature. Saturated sodium hydrogen carbonate
solution (30 ml) was then added to the solution, and extraction
with ethyl acetate (2.times.30 ml) was carried out. The combined
organic phases were dried over sodium sulfate and concentrated in
vacuo, and the residue was purified by flash chromatography with
cyclohexane/ethyl acetate (3:1).
Yield: 4.62 g (83%)
.sup.1H-NMR (DMSO-d.sub.6): 1.71 (td, 2H); 2.09 (s, 3H); 2.44 (s,
3H); 2.59 (s, 3H); 2.65 (s, 3H); 2.99 (dd, 2H); 3.08 (t, 2H); 3.83
(s, 3H); 6.85 (s, 1H); 7.06 (d, 2H); 7.19 (t, 1H); 7.37 (t, 2H);
7.70 (t, 1H).
The following ureas were prepared:
N--(3-{3-[4-(Dimethylaminophenylmethyl)cyclohexyl]ureido}propyl)-4-methoxy-
-2,3,6,N-tetramethylbenzenesulfonamide
Example 1
A solution of 4-((dimethylamino)(phenyl)methyl)cyclohexanamine A1
(439 mg, 1.89 mmol) and phenyl
3-(4-methoxy-N,2,3,6-tetramethylphenylsulfonamido)-propylcarbamate
V1 (794 mg, 1.89 mmol) in 1,4-dioxane (10 ml) was stirred for 1 d
at 110.degree. C. The solvent was then removed in vacuo and the
residue was purified by flash chromatography with
chloroform/methanol/triethylamine (100:5:1).
Yield: 700 mg (66%) 2 isomers
.sup.1H-NMR (DMSO-d.sub.6): 0.94 (m, 5H); 1.33 (m, 2H); 1.55 (m,
2H); 1.67 (d, 1H); 1.81 (d, 1H); 1.99 (s, 6H); 2.08 (s, 3H); 2.41
(s, 3H); 2.56 (s, 3H); 2.60 (s, 3H); 2.89 (m, 2H); 3.00 (m, 2H);
3.22 (d, 1H); 3.59 (m, 1H); 3.83 (s, 3H); 5.62 (m, 0.5H); 5.69 (m,
0.5H); 5.78 (d, 1H); 6.82 (s, 1H); 7.13 (d, 2H); 7.26 (dd, 1H);
7.33 (dt, 2H).
(N--(3-(3-((4-((dimethylamino)(phenyl)methyl)cyclohexyl)methyl)ureido)prop-
yl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide
Example 2
A solution of
1-(4-(aminomethyl)cyclohexyl)-N,N-dimethyl-1-phenylmethanamine A12
(200 mg, 0.81 mmol) and phenyl
3-(4-methoxy-N,2,3,6-tetramethylphenylsulfonamido)-propylcarbamate
V1 (366 mg, 0.81 mmol) in 1,4-dioxane (10 ml) was stirred for 1 d
at 110.degree. C. The solvent was then removed in vacuo and the
residue was purified by flash chromatography with
chloroform/methanol/triethylamine (100:5:1).
Yield: 351 mg (76%)
.sup.1H-NMR (DMSO-d.sub.6): 0.78 (m, 4H); 1.17 (t, 2H); 1.36 (d,
1H); 1.56 (td, 3H); 1.70 (d, 1H); 1.84 (d, 1H); 1.99 (s, 6H); 2.08
(s, 3H); 2.41 (s, 3H); 2.56 (s, 3H); 2.59 (s, 3H); 2.78 (t, 2H);
2.90 (dd, 2H); 3.02 (m, 2H); 3.37 (d, 1H); 3.83 (s, 3H); 5.70 (t,
1H); 5.78 (d, 1H); 6.82 (s, 1H); 7.13 (t, 2H); 7.24 (m, 1H); 7.31
(m, 2H).
4-Methoxy-2,3,6,N-tetramethyl-N--(3-{3-[4-(phenylpyrrolidin-1-ylmethyl)
-cyclohexyl]-ureido}propyl)benzenesulfonamide
Example 3
A solution of 4-(phenyl(pyrrolidin-1-yl)methyl)cyclohexanamine A9
(268 mg, 1.03 mmol) and phenyl
3-(4-methoxy-N,2,3,6-tetramethylphenylsulfonamido) -propylcarbamate
V1 (469 mg, 1.03 mmol) in 1,4-dioxane (10 ml) was stirred for 1 d
at 110.degree. C. The solvent was then removed in vacuo and the
residue was purified by flash chromatography with
chloroform/methanol/triethylamine (100:2:1.fwdarw.100:5:1).
Yield: 210 mg (35%)
.sup.1H-NMR (DMSO-d.sub.6): 0.61 (dd, 1H); 0.78 (m, 1H); 1.02 (m,
3H) 1.56 (m, 7H); 1.73 (d, 4H); 2.08 (s, 3H); 2.33 (m, 4H); 2.40
(s, 3H); 2.56 (s, 3H); 2.59 (s, 3H); 2.86 (dd, 2H); 2.99 (m, 2H);
3.09 (d, 1H); 3.83 (s, 3H); 5.59 (t, 1H); 5.64 (t, 1H); 6.81 (s,
1H); 7.16-7.19 (m, 2H); 7.22-7.25 (m, 1H); 7.29-7.31 (m, 2H).
4-(Dimethylaminophenylmethyl)piperidin-1-carboxylic acid
{3-[(4-methoxy-2,3,6-trimethylbenzenesulfonyl)methylamino]propyl}amide
Example 4
A solution of N,N-dimethyl-1-phenyl-1-(piperidin-4-yl)methanamine
A28 (300 mg, 1.37 mmol) and phenyl
3-(4-methoxy-N,2,3,6-tetramethylphenylsulfonamido)-propylcarbamate
V1 (621 mg, 1.37 mmol) in 1,4-dioxane (10 ml) was stirred for 1 d
at 110.degree. C. The solvent was then removed in vacuo and the
residue was purified by flash chromatography with
chloroform/methanol/triethylamine (100:5:1). Yield: 425 mg
(57%)
.sup.1H-NMR (DMSO-d.sub.6): 0.77 (ddd, 2H); 0.91 (ddd, 2H); 1.20
(d, 1H); 1.58 (m, 2H); 1.88 (d, 1H); 2.01 (s, 6H); 2.08 (s, 3H);
2.41 (s, 3H); 2.56 (s, 3H); 2.61 (s, 3H); 2.63 (d, 1H); 2.90 (dd,
2H); 2.97 (m, 2H); 3.08 (d, 1H); 3.75 (d, 1H); 3.83 (s, 3H); 3.89
(d, 1H); 6.24 (t, 1H); 6.82 (s, 1H); 7.14 (d, 2H); 7.25 (t, 1H);
7.33 (t, 2H).
Amides
The following examples were prepared in individual syntheses.
N--(4-((Dimethylamino)(phenyl)methyl)cyclohexyl)-5-(2,4,6-trichloro-N-meth-
ylphenylsulfonamido)pentanamide
Example 5
A solution of
5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoic acid S10
(250 mg, 0.667 mmol), N-methylmorpholine (201 mg, 218 .mu.l, 2.0
mmol) and 1-benzotriazolyloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (381 mg, 0.867 mmol) in anhydrous
N,N-dimethylformamide (10 ml) was stirred for one hour, and then a
solution of 4-((dimethylamino)(phenyl)methyl)cyclohexanamine A1
(174 mg, 1.0 mmol) was added thereto, and stirring was carried out
for 18 h at room temperature. The reaction mixture was then
concentrated in vacuo, and the residue was taken up in water and
adjusted to pH 8 with 5% sodium hydrogen carbonate solution. The
mixture was extracted with ethyl acetate (3.times.40 ml), and the
combined organic phases were dried over sodium sulfate and
concentrated in vacuo. The crude product was purified by flash
chromatography with chloroform/methanol (95:5).
Yield: 122 mg (31%), yellowish oil
.sup.1H-NMR (CDCl.sub.3): 1.40-2.18 (m, 14H); 2.08 and 2.10 (2 s,
6H); 2.87 and 2.88 (2 s, 3H); 3.02 (d, 0.35); 3.22-3.35 (m, 3.65H);
3.94-4.04 (m, 1H); 5.58 (d, 0.35H); 5.80 (d, 0.65H); 7.06-7.14 (m,
2H); 7.20-7.35 (m, 3H); 7.45 and 7.46 (2 s, 2H).
N--(4-(Phenyl(piperidin-1-yl)methyl)cyclohexyl)-5-(2,4,6-trichloro-N-methy-
lphenylsulfonamido)pentanamide
Example 6
A solution of
5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoic acid S10
(374 mg, 1.0 mmol), N-methylmorpholine (302 mg, 328 .mu.l, 2.9
mmol) and 1-benzotriazolyloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (571 mg, 1.3 mmol) in anhydrous
N,N-dimethylformamide (10 ml) was stirred for one hour, and then a
solution of 4-(phenyl(piperidin-1-yl)methyl)cyclohexanamine A10
(302 mg, 1.11 mmol) in anhydrous N,N-dimethylformamide (5 ml) was
added thereto and stirring was carried out for 18 h at room
temperature. The reaction mixture was then concentrated in vacuo,
and the residue was taken up in water and adjusted to pH 8 with 5%
sodium hydrogen carbonate solution. The mixture was extracted with
ethyl acetate (3.times.40 ml), and the combined organic phases were
dried over sodium sulfate and concentrated in vacuo. The crude
product was purified by flash chromatography with
chloroform/methanol (95:5). Yield: 128 mg (21%)
.sup.1H-NMR (DMSO-d.sub.6): 1.00-2.30 (m, 26H); 2.84 (m, 3H);
3.19-3.26 (m, 2H); 3.74 (br s, 1H); 7.09-7.15 (m, 2H); 7.25 (d,
0.5H); 7.28-7.36 (m, 3H); 7.55 (d, 0.5H); 7.86 and 7.88 (2 s,
2H).
N--((4-((Dimethylamino)(phenyl)methyl)cyclohexyl)methyl)-5-(2,4,6-trichlor-
o-N -methylphenylsulfonamido)pentanamide
Example 7
N,N'-Carbonyldiimidazole (248 mg, 1.45 mmol) was added to a
solution of 5-(2,4,6-trichloro-N-methylphenylsulfonamido)pentanoic
acid S10 (495 mg, 1.32 mmol) in anhydrous THF (10 ml), and stirring
was carried out for 1 h at room temperature. A solution of
1-(4-(aminomethyl)cyclohexyl)-N,N-dimethyl-1-phenylmethanamine A12
(357 mg, 1.45 mmol) in anhydrous THF (10 ml) was then added. The
reaction mixture was stirred for 18 h at room temperature and then
concentrated in vacuo; 5% sodium hydrogen carbonate solution (50
ml) was added to the residue, and extraction with ethyl acetate
(3.times.50 ml) was carried out. The combined organic phases were
dried over sodium sulfate and concentrated in vacuo. The crude
product was purified by flash chromatography with
chloroform/methanol (9:1).
Yield: 638 mg (80%)
.sup.1H-NMR (DMSO-d.sub.6): 0.60-1.95 (m, 13H); 1.99 (s, 6H); 2.05
(t, 2H); 2.82 (s, 3H), 2.85-2.99 (m, 2H); 3.00 (d, 1H); 3.21 (t,
2H); 7.15-7.40 (m, 5H); 7.68 (t, 1H), 7.85 (s, 2H).
N--((4-((Dimethylamino)(phenyl)methyl)cyclohexyl)methyl)-2-(1-(3-(trifluor-
omethyl)phenylsulfonyl)piperidin-2-yl)acetamide
Example 8
N,N'-Carbonyldiimidazole (188 mg, 1.1 mmol) was added to a solution
of 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)acetic
acid S8 (351 mg, 1 mmol) in anhydrous THF (10 ml), and stirring was
carried out for 1 h at room temperature. A solution of
1-(4-(aminomethyl)cyclohexyl-N,N-dimethyl-1-phenylmethanamine A12
(271 mg, 1.1 mmol) in anhydrous THF (10 ml) was then added to the
mixture, and stirring was carried out for 18 h at room temperature.
The reaction mixture was concentrated in vacuo, 5% sodium hydrogen
carbonate solution was added to the residue, and extraction with
ethyl acetate (3.times.30 ml) was carried out. The combined organic
phases were dried over sodium sulfate and concentrated in vacuo.
The crude product was purified by flash chromatography with
chloroform/methanol (9:1).
Yield: 298 mg (51%)
.sup.1H-NMR (DMSO-d.sub.6): 0.50-1.90 (m, 16H); 1.98 (s, 6H); 2.19
(dd, 1H), 2.43 (dd, 1H); 2.65-2.85 (m, 1.5H); 2.85-3.10 (m, 1.5H);
3.68 (br d, 1H); 4.43 (m, 1H); 7.05-7.38 (m, 5H); 7.70-7.88 (m,
2H); 7.95-8.20 (m, 2H).
Automated Synthesis
Method A
On an Accelerator SLT106 from Chemspeed, 105 .mu.mol of CDI
solution (0.105 M in DCM, 1 ml) were first introduced at room
temperature into the reactors, the appropriate acid solution (0.05
M in DCM, 2 ml) was added, and the whole was agitated for 1 h at
room temperature. 100 .mu.mol of the appropriate amine (0.1 M in
DCM, 1 ml) were then added at room temperature, and the whole was
agitated for a further 12 h at RT.
When the reaction was complete, 3 ml of water were added, the whole
was agitated for 15 min, and then the organic phase was separated.
The solvent was removed in a Genevac vacuum centrifuge and the
products were purified by means of HPLC.
Method B
Using the installation from Zymark, 100 .mu.mol of acid solution
(0.05 M in DCM, 2 ml) were placed in a dry screw-cap jar at RT, and
105 .mu.mol of CDI solution (0.105 M in DCM, 1 ml) were added
thereto. After a stirring time of 1 hour at RT, 100 .mu.mol of the
appropriate amine (0.1 M in DCM) were added to the reaction
solution by means of a pipette. The reaction solution was stirred
for 16 h at RT. Then 3 ml of water were added and thorough mixing
was carried out for 30 min. The magnetic stirrer bar was filtered
off and the vessel was rinsed with 1.5 ml of DCM.
The aqueous phase was removed and discarded. 3 ml of dist. H.sub.2O
and 0.5 ml of DCM were added to the organic phase, and the mixture
was vortexed and mixed thoroughly and intensively. After
centrifugation, the aqueous phase was separated off and discarded.
The organic phase was extracted a second time in an analogous
manner with 3 ml of sat. NaCl solution. Then the organic phase was
removed, placed in a test tube and dried over a MgSO.sub.4
cartridge. The solution was concentrated in a vacuum centrifuge
(GeneVac), and the products were purified by means of HPLC.
Method C
In parallel synthesis, the acid structural unit (50 mg, 1 eq.) was
dissolved in DCM (3 ml/mmol), and the amine structural unit (1.2
eq.), EDCI (1.5 eq.), HOBt (1 eq.) and DIPEA (2 eq.) were added
thereto. The resulting crude products were purified using a
parallel purification system from Biotage. The following compounds
were synthesised by these methods. The target mass was confirmed in
all cases as M+1 by mass spectroscopy:
TABLE-US-00004 No. Amine Acid Method Mass + 1 Name 9 A1 S15 A 576.3
N-[4-(Dimethylamino-phenyl-methyl)-cyclohexyl]-2-
[2-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-
isoquinolin-1-yl]-acetamide 10 A1 S1 A 614.2
2-[2-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-N-[4-(dimethylamino-
phenyl-methyl)-cyclohexyl]-acetamide 11 A1 S3 A 574.2
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
[4-(dimethylamino-phenyl-methyl)-cyclohexyl]- benzamide 12 A1 S6 A
634.2 2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid
[4-(dimethylamino-phenyl-methyl)-cyclohexyl]- amide 13 A3 S15 A
594.3 N-{4-[Dimethylamino-(3-fluoro-phenyl)-methyl]-
cyclohexyl}-2-[2-(4-methoxy-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide 14 A2 S15 A 594.3
N-{4-[Dimethylamino-(4-fluoro-phenyl)-methyl]-
cyclohexyl}-2-[2-(4-methoxy-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide 15 A4 S15 A 582.2
N-[4-(Dimethylamino-thiophen-2-yl-methyl)-
cyclohexyl]-2-[2-(4-methoxy-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide 16 A14 S15 A 608.3
N-{4-[Dimethylamino-(3-fluoro-phenyl)-methyl]-
cyclohexylmethyl}-2-[2-(4-methoxy-benzene-
sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- acetamide 17 A12
S15 A 590.3 N-[4-(Dimethylamino-phenyl-methyl)-cyclohexyl-
methyl]-2-[2-(4-methoxy-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-acetamide 18 A17 S15 A 618.3
N-[4-(1-Dimethylamino-3-phenyl-propyl)-cyclohexyl-
methyl]-2-[2-(4-methoxy-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-acetamide 19 A13 S15 A 608.3
N-{4-[Dimethylamino-(4-fluoro-phenyl)-methyl]-
cyclohexylmethyl}-2-[2-(4-methoxy-benzene-
sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- acetamide 20 A15
S15 A 624.3 N-{4-[(4-Chloro-phenyl)-dimethylamino-methyl]-
cyclohexylmethyl}-2-[2-(4-methoxy-benzene-
sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- acetamide 21 A16
S15 A 596.3 N-[4-(Dimethylamino-thiophen-2-yl-methyl)-
cyclohexylmethyl]-2-[2-(4-methoxy-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide 22 A25 S15 A 638.3
N-(2-{4-[(4-Chloro-phenyl)-dimethylamino-methyl]-
cyclohexyl}-ethyl)-2-[2-(4-methoxy-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide 23 A24 S15 A 622.3
N-(2-{4-[Dimethylamino-(3-fluoro-phenyl)-methyl]-
cyclohexyl}-ethyl)-2-[2-(4-methoxy-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide 24 A23 S15 A 622.3
N-(2-{4-[Dimethylamino-(4-fluoro-phenyl)-methyl]-
cyclohexyl}-ethyl)-2-[2-(4-methoxy-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide 25 A26 S15 A 610.3
N-{2-[4-(Dimethylamino-thiophen-2-yl-methyl)-
cyclohexyl]-ethyl}-2-[2-(4-methoxy-benzenesulfonyl)-
1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetamide 26 A3 S1 A 632.2
2-(2-(3,4-Dichlorophenylsulfonyl)-1,2,3,4-tetra-
hydroisoquinolin-1-yl)-N-(4-((dimethylamino)(3-
fluorophenyl)methyl)cyclohexyl)acetamide 27 A2 S1 A 632.2
2-(2-(3,4-Dichlorophenylsulfonyl)-1,2,3,4-tetra-
hydroisoquinolin-1-yl)-N-(4-((dimethylamino)(4-
fluorophenyl)methyl)cyclohexyl)acetamide 28 A14 S1 A 646.2
2-[2-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-N-{4-[dimethylamino-(3-
fluoro-phenyl)-methyl]-cyclohexylmethyl}-acetamide 29 A12 S1 A
628.2 2-[2-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-N-[4-(dimethylamino-
phenyl-methyl)-cyclohexylmethyl]-acetamide 30 A17 S1 A 656.2
2-[2-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-N-[4-(1-dimethylamino-3-
phenyl-propyl)-cyclohexylmethyl]-acetamide 31 A13 S1 A 646.2
2-[2-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-N-{4-[dimethylamino-(4-
fluoro-phenyl)-methyl]-cyclohexylmethyl}-acetamide 32 A15 S1 A
662.2 N-{4-[(4-Chloro-phenyl)-dimethylamino-methyl]-
cyclohexylmethyl}-2-[2-(3,4-dichloro-benzene-
sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- acetamide 33 A25 S1
A 676.2 N-(2-{4-[(4-Chloro-phenyl)-dimethylamino-methyl]-
cyclohexyl}-ethyl)-2-[2-(3,4-dichloro-benzene-
sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]- acetamide 34 A24 S1
A 660.2 2-[2-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-N-(2-{4-[dimethylamino-
(3-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)- acetamide 35 A23 S1 A
660.2 2-[2-(3,4-Dichloro-benzenesulfonyl)-1,2,3,4-
tetrahydro-isoquinolin-1-yl]-N-(2-{4-[dimethylamino-
(4-fluoro-phenyl)-methyl]-cyclohexyl}-ethyl)- acetamide 36 A3 S4 A
592.2 2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
{4-[dimethylamino-(3-fluoro-phenyl)-methyl]- cyclohexyl}-benzamide
37 A2 S4 A 592.2 2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
{4-[dimethylamino-(4-fluoro-phenyl)-methyl]- cyclohexyl}-benzamide
38 A12 S4 A 588.2
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
[4-(dimethylamino-phenyl-methyl)-cyclohexylmethyl]- benzamide 39
A17 S4 A 616.2 2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
[4-(1-dimethylamino-3-phenyl-propyl)-cyclohexyl- methyl]-benzamide
40 A13 S4 A 606.2
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-
cyclohexylmethyl}-benzamide 41 A15 S4 A 622.1
N-{4-[(4-Chloro-phenyl)-dimethylamino-methyl]-
cyclohexylmethyl}-2-[(3,4-dichloro-benzenesulfonyl)-
methyl-amino]-benzamide 42 A16 S4 A 594.1
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
[4-(dimethylamino-thiophen-2-yl-methyl)-cyclohexyl-
methyl]-benzamide 43 A25 S4 A 636.2
N-(2-{4-[(4-Chloro-phenyl)-dimethylamino-methyl]-
cyclohexyl}-ethyl)-2-[(3,4-dichloro-benzenesulfonyl)-
methyl-amino]-benzamide 44 A24 S4 A 620.2
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
(2-{4-[dimethylamino-(3-fluoro-phenyl)-methyl]-
cyclohexyl}-ethyl)-benzamide 45 A23 S4 A 620.2
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-N-
(2-{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-
cyclohexyl}-ethyl)-benzamide 46 A12 S5 A 648.2
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid
[4-(dimethylamino-phenyl-methyl)-cyclohexyl- methyl]-amide 47 A13
S5 A 666.2 2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid
{4-[dimethylamino-(4-fluoro-phenyl)-methyl]-
cyclohexylmethyl}-amide 48 A15 S5 A 682.1
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid
{4-[(4-chloro-phenyl)-dimethylamino-methyl]-
cyclohexylmethyl}-amide 49 A16 S5 A 654.1
2-[(3,4-Dichloro-benzenesulfonyl)-methyl-amino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid
[4-(dimethylamino-thiophen-2-yl-methyl)- cyclohexylmethyl]-amide 50
A25 S5 A 696.2 N-(2-(4-((4-Chlorophenyl)(dimethylamino)methyl)-
cyclohexyl)ethyl)-2-(3,4-dichloro-N-methylphenyl-
sulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide 51
A24 S5 A 680.2 2-(3,4-Dichloro-N-methylphenylsulfonamido)-N-(2-(4-
((dimethylamino)(3-fluorophenyl)methyl)cyclohexyl)-
ethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide 52 A23 S5
A 680.2 2-(3,4-Dichloro-N-methylphenylsulfonamido)-N-(2-(4-
((dimethylamino)(4-fluorophenyl)methyl)cyclohexyl)-
ethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide 53 A26 S5
A 668.2 2-(3,4-Dichloro-N-methylphenylsulfonamido)-N-(2-(4-
((dimethylamino)(thiophen-2-yl)methyl)cyclohexyl)-
ethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxamide 54 A11
S12 C 671.2 2-[1-(3,4-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-
tetrahydro-quinoxalin-2-yl]-N-[4-(morpholin-4-yl-
phenyl-methyl)-cyclohexyl]-acetamide 55 A18 S11 C 637.2
2-[1-(2,4-Dichloro-benzenesulfonyl)-3-oxo-piperazin-
2-yl]-N-[4-(morpholin-4-yl-phenyl-methyl)-cyclohexyl-
methyl]-acetamide 56 A19 S11 C 665.2
2-[1-(2,4-Dichloro-benzenesulfonyl)-3-oxo-piperazin-
2-yl]-N-[4-(1-morpholin-4-yl-3-phenyl-propyl)-
cyclohexylmethyl]-acetamide 57 A21 S11 C 649.2
2-[1-(2,4-Dichloro-benzenesulfonyl)-3-oxo-piperazin-
2-yl]-N-[4-(3-phenyl-1-pyrrolidin-1-yl-propyl)-
cyclohexylmethyl]-acetamide 58 A20 S11 C 621.2
2-[1-(2,4-Dichloro-benzenesulfonyl)-3-oxo-piperazin-
2-yl]-N-[4-(phenyl-pyrrolidin-1-yl-methyl)-cyclohexyl-
methyl]-acetamide 59 A7 S11 C 649.2
2-[1-(2,4-Dichloro-benzenesulfonyl)-3-oxo-piperazin-
2-yl]-N-[4-(3-phenyl-1-piperidin-1-yl-propyl)-cyclo-
hexyl]-acetamide 60 A6 S11 C 651.2
2-[1-(2,4-Dichloro-benzenesulfonyl)-3-oxo-piperazin-
2-yl]-N-[4-(1-morpholin-4-yl-3-phenyl-propyl)-
cyclohexyl]-acetamide 61 A8 S11 C 636.2
2-[1-(2,4-Dichloro-benzenesulfonyl)-3-oxo-piperazin-
2-yl]-N-{4-[(4-methyl-piperazin-1-yl)-phenyl-methyl]-
cyclohexyl}-acetamide 62 A29 S11 C 609.2
4-(2,4-Dichloro-benzenesulfonyl)-3-{2-[4-(morpholin-
4-yl-phenyl-methyl)-piperidin-1-yl]-2-oxo-ethyl}- piperazin-2-one
63 A30 S11 C 623.2
4-(2,4-Dichlorophenylsulfonyl)-3-(2-(2-(1-morpholino-
2-phenylethyl)piperidin-1-yl)-2-oxoethyl)piperazin-2- one 64 A18
S12 C 685.2 2-[1-(3,4-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-
tetrahydro-quinoxalin-2-yl]-N-[4-(morpholin-4-yl-
phenyl-methyl)-cyclohexylmethyl]-acetamide 65 A19 S12 C 713.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-
tetrahydro-quinoxalin-2-yl]-N-[4-(1-morpholin-4-yl-3-
phenyl-propyl)-cyclohexylmethyl]-acetamide 66 A21 S12 C 697.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-
tetrahydro-quinoxalin-2-yl]-N-[4-(3-phenyl-1-
pyrrolidin-1-yl-propyl)-cyclohexylmethyl]-acetamide 67 A20 S12 C
669.2 2-[1-(3,4-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-
tetrahydro-quinoxalin-2-yl]-N-[4-(phenyl-pyrrolidin-1-
yl-methyl)-cyclohexylmethyl]-acetamide 68 A7 S12 C 697.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-
tetrahydro-quinoxalin-2-yl]-N-[4-(3-phenyl-1-
piperidin-1-yl-propyl)-cyclohexyl]-acetamide 69 A6 S12 C 699.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-
tetrahydro-quinoxalin-2-yl]-N-[4-(1-morpholin-4-yl-3-
phenyl-propyl)-cyclohexyl]-acetamide 70 A8 S12 C 684.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-
tetrahydro-quinoxalin-2-yl]-N-{4-[(4-methyl-piperazin-
1-yl)-phenyl-methyl]-cyclohexyl}-acetamide 71 A29 S12 C 657.2
4-(3,4-Dichloro-benzenesulfonyl)-3-{2-[4-(morpholin-
4-yl-phenyl-methyl)-piperidin-1-yl]-2-oxo-ethyl}-3,4-
dihydro-1H-quinoxalin-2-one 72 A30 S12 C 671.2
4-(3,4-Dichlorophenylsulfonyl)-3-(2-(4-(1-morpholino-
2-phenylethyl)piperidin-1-yl)-2-oxoethyl)-3,4-
dihydroquinoxalin-2(1H)-one 73 A18 S13 C 608.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-
N-[4-(morpholin-4-yl-phenyl-methyl)-cyclohexyl- methyl]-acetamide
74 A19 S13 C 636.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-
N-[4-(1-morpholin-4-yl-3-phenyl-propyl)-cyclohexyl-
methyl]-acetamide 75 A21 S13 C 620.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-
N-[4-(3-phenyl-1-pyrrolidin-1-yl-propyl)-cyclohexyl-
methyl]-acetamide 76 A20 S13 C 592.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-
N-[4-(phenyl-pyrrolidin-1-yl-methyl)-cyclohexyl- methyl]-acetamide
77 A7 S13 C 620.2
2-(1-(3,4-Dichlorophenylsulfonyl)pyrrolidin-2-yl)-N-(4-
(3-phenyl-1-(piperidin-1-yl)propyl)cyclohexyl)- acetamide 78 A6 S13
C 622.2 2-(1-(3,4-Dichlorophenylsulfonyl)pyrrolidin-2-yl)-N-(4-
(1-morpholino-3-phenylpropyl)cyclohexyl)acetamide 79 A8 S13 C 607.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-
N-{4-[(4-methyl-piperazin-1-yl)-phenyl-methyl]-
cyclohexyl}-acetamide 80 A29 S13 C 580.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-
1-[4-(morpholin-4-yl-phenyl-methyl)-piperidin-1-yl]- ethanone 81
A30 S13 C 594.2
2-(1-(3,4-Dichlorophenylsulfonyl)pyrrolidin-2-yl)-1-(4--
(1-morpholino-2-phenylethyl)piperidin-1-yl)ethanone 82 A18 S14 C
622.2 2-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-2-yl]-N-
[4-(morpholin-4-yl-phenyl-methyl)-cyclohexylmethyl]- acetamide 83
A19 S14 C 650.3
2-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-2-yl]-N-
[4-(1-morpholin-4-yl-3-phenyl-propyl)-cyclohexyl- methyl]-acetamide
84 A21 S14 C 634.3
2-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-2-yl]-N-
[4-(3-phenyl-1-pyrrolidin-1-yl-propyl)-cyclohexyl-
methyl]-acetamide 85 A20 S14 C 606.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-2-yl]-N-
[4-(phenyl-pyrrolidin-1-yl-methyl)-cyclohexylmethyl]- acetamide
86 A7 S14 C 634.3
2-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-2-yl]-N-
[4-(3-phenyl-1-piperidin-1-yl-propyl)-cyclohexyl]- acetamide 87 A6
S14 C 636.2 2-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-2-yl]-N-
[4-(1-morpholin-4-yl-3-phenyl-propyl)-cyclohexyl]- acetamide 88 A8
S14 C 621.2 2-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-2-yl]-N-
{4-[(4-methyl-piperazin-1-yl)-phenyl-methyl]- cyclohexyl}-acetamide
89 A29 S14 C 594.2
2-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-2-yl]-1-
[4-(morpholin-4-yl-phenyl-methyl)-piperidin-1-yl]- ethanone 90 A30
S14 C 608.2 2-(1-(3,4-Dichlorophenylsulfonyl)piperidin-2-yl)-1-(4-
(1-morpholino-2-phenylethyl)piperidin-1-yl)ethanone 91 A1 S6 B
586.2 1-(3,4-Dichlorophenylsulfonyl)-N-(4-((dimethyl-
amino)(phenyl)methyl)cyclohexyl)indoline-2- carboxamide 92 A3 S6 B
604.2 1-(3,4-Dichlorophenylsulfonyl)-N-(4-((dimethyl-
amino)(3-fluorophenyl)methyl)cyclohexyl)indoline-2- carboxamide 93
A5 S6 B 614.2 1-(3,4-Dichlorophenylsulfonyl)-N-(4-(1-(dimethyl-
amino)-3-phenylpropyl)cyclohexyl)indoline-2- carboxamide 94 A2 S6 B
604.2 1-(3,4-Dichlorophenylsulfonyl)-N-(4-((dimethyl-
amino)(4-fluorophenyl)methyl)cyclohexyl)indoline-2- carboxamide 95
A12 S6 B 600.2 1-(3,4-Dichlorophenylsulfonyl)-N-((4-((dimethyl-
amino)(phenyl)methyl)cyclohexyl)methyl)indoline-2- carboxamide 96
A17 S6 B 628.2 1-(3,4-Dichlorophenylsulfonyl)-N-((4-(1-(dimethyl-
amino)-3-phenylpropyl)cyclohexyl)methyl)indoline-2- carboxamide 97
A27 S6 B 642.2 1(3,4-Dichlorophenylsulfonyl)-N-(2-(4-(1-(dimethyl-
amino)-3-phenylpropyl)cyclohexyl)ethyl)indoline-2- carboxamide 98
A22 S2 B 616.2 2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)-
phenyl)-N-(2-(4-((dimethylamino)(phenyl)-
methyl)cyclohexyl)ethyl)acetamide 99 A27 S2 B 644.2
2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)-
phenyl)-N-(2-(4-(1-(dimethylamino)-3-phenylpropyl)-
cyclohexyl)ethyl)acetamide 100 A22 S9 B 570.3
N-(2-(4-((Dimethylamino)(phenyl)methyl)cyclohexyl)-
ethyl)-1-(4-methoxy-N-methylphenylsulfonamido)-
cyclohexanecarboxamide 101 A11 S11 C 623.2
2-(1-(2,4-Dichlorophenylsulfonyl)-3-oxopiperazin-2-
yl)-N-(4-(morpholino(phenyl)methyl)cyclohexyl)- acetamide 102 A9
S11 C 607.2 2-(1-(2,4-Dichlorophenylsulfonyl)-3-oxopiperazin-2-
yl)-N-(4-(phenyl(pyrrolidin-1-yl)methyl)cyclohexyl)- acetamide 103
A9 S12 C 655.2 2-(1-(3,4-Dichlorophenylsulfonyl)-3-oxo-1,2,3,4-
tetrahydroquinoxalin-2-yl)-N-(4-(phenyl(pyrrolidin-1-
yl)methyl)cyclohexyl)acetamide 104 A11 S13 C 594.2
2-(1-(3,4-Dichlorophenylsulfonyl)pyrrolidin-2-yl)-N-(4- -
(morpholino(phenyl)methyl)cyclohexyl)acetamide 105 A9 S13 C 578.2
2-(1-(3,4-Dichlorophenylsulfonyl)pyrrolidin-2-yl)-N-(4--
(phenyl(pyrrolidin-1-yl)methyl)cyclohexyl)acetamide 106 A11 S14 C
608.2 2-(1-(3,4-Dichlorophenylsulfonyl)piperidin-2-yl)-N-(4--
(morpholino(phenyl)methyl)cyclohexyl)acetamide 107 A9 S14 C 592.2
2-(1-(3,4-Dichlorophenylsulfonyl)piperidin-2-yl)-N-(4-
(phenyl(pyrrolidin-1-yl)methyl)cyclohexyl)acetamide 108 A33 S8 C
607.3 1-(4-((4-Methylpiperazin-1-yl)(phenyl)methyl)-
piperidin-1-yl)-2-(1-(3-(trifluoromethyl)-phenyl-
sulfonyl)piperidin-2-yl)ethanone 109 A32 S8 C 625.3
1-(4-((4-Fluorophenyl)(4-methylpiperazin-1-
yl)methyl)piperidin-1-yl)-2-(1-(3-(trifluoromethyl)-
phenylsulfonyl)piperidin-2-yl)ethanone 110 A31 S16 C 629.3
N-(3-(4-((3-Fluorophenyl)(4-methylpiperazin-1-
yl)methyl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-
naphthalene-2-sulfonamide 111 A34 S8 C 621.3
1-(4-(1-(4-Methylpiperazin-1-yl)-2-phenylethyl)-
piperidin-1-yl)-2-(1-(3-(trifluoromethyl)phenyl-
sulfonyl)piperidin-2-yl)ethanone 112 A35 S8 C 621.3
1-(4-(1-(4-Methylpiperazin-1-yl)-3-phenylpropyl)-
piperidin-1-yl)-2-(1-(3-(trifluoromethyl)phenyl-
sulfonyl)piperidin-2-yl)ethanone 113 A35 S16 C 635.3
N-(3-(4-(1-(4-Methylpiperazin-1-yl)-3-phenylpropyl)-
piperidin-1-yl)-3-oxo-1-phenylpropyl)naphthalene-2- sulfonamide 114
A33 S16 C 639.3 N-(3-(4-((4-Methylpiperazin-1-yl)(phenyl)methyl)-
piperidin-1-yl)-3-oxo-1-phenylpropyl)naphthalene-2- sulfonamide 115
A31 S8 C 611.3 1-(4-((3-Fluorophenyl)(4-methylpiperazin-1-yl)-
methyl)piperidin-1-yl)-2-(1-(3-(trifluoromethyl)-
phenylsulfonyl)piperidin-2-yl)ethanone 116 A34 S16 C 625.3
N-(3-(4-(1-(4-Methylpiperazin-1-yl)-2-phenylethyl)-
piperidin-1-yl)-3-oxo-1-phenylpropyl)naphthalene-2- sulfonamide 117
A32 S16 C 626.3 N-(3-(4-((4-Fluorophenyl)(4-methylpiperazin-1-yl)-
methyl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-
naphthalene-2-sulfonamide 118 A34 S17 C 629.3
3-(1-(4-Chloro-2,5-dimethylphenylsulfonyl)piperidin-
2-yl)-1-(4-(1-(4-methylpiperazin-1-yl)-2-phenylethyl)-
piperidin-1-yl)propan-1-one 119 A35 S17 C 630.3
3-(1-(4-Chloro-2,5-dimethylphenylsulfonyl)piperidin-
2-yl)-1-(4-(1-(4-methylpiperazin-1-yl)-3-
phenylpropyl)piperidin-1-yl)propan-1-one 120 A31 S17 C 643.3
3-(1-(4-Chloro-2,5-dimethylphenylsulfonyl)piperidin-
2-yl)-1-(4-((3-fluorophenyl)(4-methylpiperazin-1-
yl)methyl)piperidin-1-yl)propan-1-one 121 A32 S17 C 633.3
3-(1-(4-Chloro-2,5-dimethylphenylsulfonyl)piperidin-
2-yl)-1-(4-((4-fluorophenyl)(4-methylpiperazin-1-
yl)methyl)piperidin-1-yl)propan-1-one 122 A33 S17 C 633.3
3-(1-(4-Chloro-2,5-dimethylphenylsulfonyl)piperidin-
2-yl)-1-(4-((4-methylpiperazin-1-yl)(phenyl)methyl)-
piperidin-1-yl)propan-1-one
Studies of the Effectiveness of the Compounds According to the
Invention Method for determining the affinity for the human
.mu.-opiate receptor
The receptor affinity for the human .mu.-opiate receptor is
determined in a homogeneous batch on microtitre plates. To this
end, serial dilutions of the substances to be tested are incubated
for 90 minutes at room temperature with a receptor membrane
preparation (15-40 .mu.g of protein/250 .mu.l of incubation batch)
of CHO-K1 cells, which express the human .mu.-opiate receptor
(RB-HOM receptor membrane preparation from PerkinElmer Life
Sciences, Zaventem, Belgium), in the presence of 1 nmol/l of the
radioactive ligand [.sup.3H]-naloxone (NET719, PerkinElmer Life
Sciences, Zaventem, Belgium) and 1 mg of WGA-SPA beads (wheatgerm
agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in
a total volume of 250 .mu.l. The incubation buffer used is 50
mmol/l of Tris-HCl supplemented with 0.06 wt. % bovine serum
albumin. In order to determine non-specific binding, 100 .mu.mol/l
of naloxone is additionally added. When the ninety-minute
incubation time has ended, the microtitre plates are centrifuged
off for 20 minutes at 1000 g and the radioactivity is measured in a
.beta.-counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg,
Germany). The percentage displacement of the radioactive ligand
from its binding to the human .mu.-opiate receptor at a
concentration of the test substances of 1 .mu.mol/l is determined
and stated as the percentage inhibition of specific binding. On the
basis of the percentage displacement by different concentrations of
the test substances, IC.sub.50 inhibitory concentrations, which
effect 50% displacement of the radioactive ligand, are calculated.
K.sub.i values for the test substances are obtained by conversion
by means of the Cheng-Prusoff equation.
Functional Study on the Human Bradykinin Receptor 1 (B1R)
The agonistic or antagonistic action of substances can be
determined on the bradykinin receptor 1 (B1R) of the species human
and rat using the following assay. According to this assay, the
Ca.sup.2+ influx through the channel is quantified with the aid of
a Ca.sup.2+-sensitive dye (Fluo-4 type, Molecular Probes Europe BV,
Leiden, Netherlands) using a Fluorescent Imaging Plate Reader
(FLIPR, Molecular Devices, Sunnyvale, USA).
Method:
Chinese hamster ovary cells (CHO K1 cells) which have been stably
transfected with the human B1R gene (hB1R cells) or with the B1R
gene of the rat (rB1R cells) are used. For functional studies, the
cells are plated out on black 96-well plates having a clear base
(BD Biosciences, Heidelberg, Germany or Greiner, Frickenhausen,
Germany) in a density of 20,000-35,000 cells/well. The cells are
incubated overnight at 37.degree. C. and with 5% CO.sub.2 in
culture medium (hB1R cells: Nutrient Mixture Ham's F12, Gibco
Invitrogen GmbH, Karlsruhe, Germany or DMEM, Sigma-Aldrich,
Taufkirchen, Germany; rB1R cells: D-MEM/F12, Gibco Invitrogen GmbH,
Karlsruhe, Germany), with 10 vol. % FBS (fetal bovine serum, Gibco
Invitrogen GmbH, Karlsruhe, Germany or PAN Biotech GmbH, Aidenbach,
Germany).
On the following day, the cells are loaded for 60 minutes at
37.degree. C. with 2.13 .mu.M Fluo-4 (Molecular Probes Europe BV,
Leiden, Netherlands) in HBSS buffer (Hank's buffered saline
solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) with 2.5 mM
probenecid (Sigma-Aldrich, Taufkirchen, Germany) and 10 mM HEPES
(Sigma-Aldrich, Taufkirchen, Germany). The plates are then washed
twice with HBSS buffer, and HBSS buffer additionally containing
0.1% BSA (bovine serum albumin; Sigma-Aldrich, Taufkirchen,
Germany), 5.6 mM glucose and 0.05% gelatin (Merck KGaA, Darmstadt,
Germany) is added to the plates. After incubation for a further 20
minutes at room temperature, the plates are inserted into the FLIPR
for Ca.sup.2+ measurement. Alternatively, washing is carried out
with buffer A (15 mM HEPES, 80 mM NaCl, 5 mM KCl, 1.2 mM
CaCl.sub.2, 0.7 mM MgSO.sub.4, 2 g/l glucose, 2.5 mM probenecid)
followed by loading with buffer A with added 2.5 .mu.M Fluo-4 and
0.025% Pluronic F127 (Sigma-Aldrich, Taufkirchen, Germany). The
cells are then washed twice with buffer A and incubated for 30
minutes at room temperature with buffer A additionally containing
0.05% BSA and 0.05% gelatin and are then inserted into the FLIPR
for Ca.sup.2+ measurement.
The Ca.sup.2+-dependent fluorescence is measured before and after
the addition of substances (.lamda..sub.ex=488 nm,
.lamda..sub.em=540 nm). Quantification is carried out by measuring
the highest fluorescence intensity (FC, fluorescence counts) over
time.
FLIPR Assay:
The FLIPR protocol consists of two substance additions. Test
substances (10 .mu.M) are first pipetted onto the cells and the
Ca.sup.2+ influx is compared with the control (hB1R:
Lys-Des-Arg.sup.9-bradykinin>=0.5 nM; rB1R:
Des-Arg.sup.9-bradykinin 10 .mu.M). This gives the activation in %,
based on the Ca.sup.2+ signal after addition of
Lys-Des-Arg.sup.9-bradykinin (>=0.5 nM) or
Des-Arg.sup.9-bradykinin (10 .mu.M).
After 10-20 minutes' incubation, Lys-Des-Arg.sup.9-bradykinin
(hB1R) or Des-Arg.sup.9-bradykinin (rB1R) is applied in the
concentration of the EC.sub.80, and the influx of Ca.sup.2+ is
likewise determined.
Antagonists lead to suppression of the Ca.sup.2+ influx. The %
inhibition compared with the maximum achievable inhibition is
calculated.
In order to determine the IC.sub.50 value, the substances are added
in various concentrations. Duplicate or triplicate determinations
(n=2 or n=3) are carried out, and these are repeated in at least
one further independent experiment (N>=2).
TABLE-US-00005 B1R antagonism, B1R antagonism, rat .mu.-Opioid
receptor human [10 .mu.M] [10 .mu.M] [1 .mu.M] Example % inhibition
% inhibition % inhibition 1 71.5 56 94 2 55.6 43 97 3 80.8 58 71 4
54.8 95 100 5 100.8 60 89 6 75.1 41 29 7 101.5 59 96 8 71.4 9 94 9
105 0 10 70.1 0 11 85.45 107 12 -- 0 13 64.4 76 14 86.9 75 15 44.6
57 16 35.5 57 17 36.6 41 18 58.8 73 19 42.7 41 20 38.8 28 21 52.9
41 22 70.3 34 23 64 57 24 82.2 67 25 79.5 68 26 97.4 73 27 102.6 78
28 26.3 34 29 64.5 45 30 75.7 58 31 54. 48 32 10.7 15 33 42.2 18 34
71.2 41 35 79.5 49 36 64.1 67 37 82.2 64 38 17.9 15 39 79.3 42 40
17.1 20 41 22. 25 42 3 43 28.9 11 44 46.5 18 45 75.7 26 46 -- -9 47
-- 12 48 -- 19 49 -- 19 50 -- 11 51 -- 1 52 -- -22 53 -- 12 54 105
44 12 55 102.9 26 24 56 103.6 20 11 57 103.9 27 25 58 103.8 11 70
59 104.1 27 61 60 103.7 8 54 61 103.8 39 34 62 -- 27 4 63 28.6 -3
47 64 104.2 29 10 65 103.3 24 9 66 102.1 96 11 67 103.8 104 64 68
103.9 37 30 69 104.8 19 7 70 104 98 11 71 104.5 32 12 72 101.6 30
26 73 76.3 36 17 74 54.7 19 7 75 91.7 2 65 76 80.4 9 84 77 101.7 1
35 78 78.3 10 18 79 96.8 33 47 80 16.7 15 7 81 65.3 56 16 82 23.5 7
23 83 37 -3 22 84 95.4 19 90 85 92.7 22 95 86 100.7 30 54 87 96.8
25 38 88 101 61 58 89 16.4 26 8.5 90 14.4 17 12 91 17.8 8 92 26 -13
93 15.5 -24 94 -- -19 95 18.6 -15 96 -- 12 97 16 11 98 66.8 -8 99
83.3 -7 100 -- -2 101 103.6 31 4 102 104.3 12 35 103 103.4 37 71
104 32.8 13 11 105 99.5 24 76 106 48.3 19 21 107 102.3 26 78 108 97
78 6 109 102 99 5 110 102 100 3 111 94 61 -2 112 90 61 28 113 97 39
21 114 93 71 40 115 87 52 11 116 102 93 7 117 -- 47 118 101 93 3
119 102 97 52 120 105 73 41 121 105 58 6 122 98 40 47
The foregoing description and examples have been set forth merely
to illustrate the invention and are not intended to be limiting.
Since modifications of the described embodiments incorporating the
spirit and substance of the invention may occur to persons skilled
in the art, the invention should be construed broadly to include
all variations within the scope of the appended claims and
equivalents thereof.
* * * * *